Pathogenesis of psoriasis and development of treatment
Lauric acid ameliorates lipopolysaccharide (LPS)-induced liver inflammation by mediating the TLR4/MyD88 pathway in Sprague Dawley (SD) rats
Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophages
Palmitate and insulin synergistically induce IL-6 expression in human monocytes
Lactic acid LA significantly suppressed LPS-induced cytokine production and NF-κB transcriptional activity in mouse bone marrow-derived mast cells and cytokine production in peritoneal mast cells.
Lactate Suppresses Macrophage/monocytes Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-κB Activation via GPR81-Mediated Signaling
Psoriasiform dermatitis is driven by IL-36–mediated DC-keratinocyte crosstalk
Pathogenesis of psoriasis and development of treatment
Eisaku Ogawa Yuki Sato Akane Minagawa Ryuhei Okuyama
First published: 10 December 2017
Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan
Abstract
The pathogenesis of psoriasis can be explained by dysregulation of immunological cell function as well as keratinocyte proliferation/differentiation. Recently, the immunological pathomechanism has been clarified substantially. Whereas T‐helper (Th)1 overactivation was thought to induce occurrence of psoriasis, it has been demonstrated that Th17 cells play a key role. Th17 development is maintained by interleukin (IL)‐23 mainly produced by dendritic cells. Th17 cells produce various cytokines, including IL‐17A, IL‐17F and IL‐22. IL‐17A and IL‐22 induce not only keratinocyte proliferation, but also tumor necrosis factor (TNF)‐α, chemokine (C‐X‐C motif) ligand (CXCL)1 and CXCL8 production. TNF‐α accelerates the infiltration of inflammatory cells, including lymphocytes, monocytes and neutrophils, from the peripheral blood into skin with dendritic cell activation. In addition, antimicrobial peptides are overexpressed in psoriatic skin lesions, and the antimicrobial peptide, LL‐37, activates dendritic cells, which leads to the development of inflammation. Furthermore, activation of nuclear factor‐κB signal induces the expression of keratins 6 and 16 in keratinocytes, which are associated with acanthosis and reduced turnover time in the epidermis. The progression of the pathomechanism contributes to the development of new therapies for psoriasis.
牛皮癣的发病机理可以通过免疫细胞功能失调以及角质形成细胞增殖/分化来解释。最近，免疫病理机制已得到实质性阐明。 T-helper（Th）1过度活化被认为可诱导牛皮癣的发生，但已证明Th17细胞起关键作用。 Th17的发育由主要由树突状细胞产生的白介素（IL）-23维持。 Th17细胞产生各种细胞因子，包括IL-17A，IL-17F和IL-22。 IL-17A和IL-22不仅诱导角质形成细胞增殖，还诱导肿瘤坏死因子（TNF）-α，趋化因子（C-X-C基序）配体（CXCL）1和CXCL8的产生。 TNF-α通过树突状细胞活化促进炎症细胞（包括淋巴细胞，单核细胞和嗜中性粒细胞）从外周血向皮肤的浸润。此外，牛皮癣皮肤病变中抗菌肽过表达，抗菌肽LL-37激活树突状细胞，导致炎症的发展。此外，核因子κB信号的激活诱导角质形成细胞中角蛋白6和16的表达，这与棘皮症和表皮周转时间缩短有关。病理机制的发展促进了牛皮癣新疗法的发展。
Introduction
Psoriasis affects approximately 2% of the world's population, but its rate in Japan is 0.1–0.2%.1-4 This difference may be attributable to racial factors. The occurrence is affected by various factors, including a heritable predisposition, environmental factors, endocrine hormones and immunological factors. Recent studies have improved our understanding of the pathogenesis of psoriasis, and facilitated the development of new drugs targeting various molecules thought to be involved. This review summarizes current knowledge and information regarding the pathogenesis of psoriasis.
Pathomechanism of Psoriasis as an Immune Disease
T‐helper 1/2
In 1979, it was reported that cyclosporin A (CsA) improved psoriatic skin eruptions, which suggested that the pathology of psoriasis is related not only to keratinocytes but also to the immune system.5 Activated CD4+ and CD8+ lymphocytes were initially considered to be equally important in the inflammation associated with psoriasis because large numbers of activated CD4+ and CD8+ lymphocytes were identified in the skin and peripheral blood of psoriatic patients.6, 7 Subsequently, CD4+ T‐helper (Th) were shown to play a more important role than CD8+ lymphocytes, because psoriasis‐like skin lesions developed in mice transplanted with activated Th cells from psoriatic patients.8, 9 Moreover, the levels of Th1 cytokines, such as γ‐interferon (IFN‐γ), tumor necrosis factor‐α (TNF‐α) and interleukin (IL)‐12, were elevated in psoriatic lesions, while no such increases in expression of Th2 cytokines (IL‐4, IL‐5 and IL‐10) were observed.10-12 These findings characterized psoriasis as a Th1‐type disease. However, keratinocyte proliferation is not induced by IFN‐γ or TNF‐α, either.13-15 The pathogenesis of psoriasis could not be fully understood based only on Th1 functions, and it was predicted that other key players should participate in its occurrence.
Th17 and Th17 cytokines
Recently, Th17 cells have attracted attention as a key player in psoriasis. Th17 has been proposed as a new Th subtype, which cannot be categorized into Th1/Th2 based on the classic paradigm and produces IL‐17A.16 IL‐17A was found as a product of activated memory CD4+ T cells.17 In addition to Th17 cells, IL‐17A is produced in small amounts by CD8+ cells, γδ‐T‐cell receptor cells and natural killer T cells.18-21 The IL‐17 cytokine family includes six members (IL‐17A to IL‐17F). IL‐17 cytokines, especially IL‐17A and IL‐17F, have roles in protection against infection by extracellular pathogens. Studies performed in IL‐17 receptor‐deficient mice indicated that IL‐17 plays important functions in protecting the host against infection by Gram‐negative bacteria and fungi.22, 23 In addition, IL‐17 is important for maintenance and recruitment of neutrophils (Fig. 1).24
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Figure 1
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Main axis of the pathogenesis of psoriasis. Cells important in the pathogenesis of psoriasis are dendritic cells (DC), T‐helper (Th)17 (and Th1), and keratinocytes. DC activated by various stimuli excessively produce and secrete tumor necrosis factor (TNF)‐α and interleukin (IL)‐23 (including IL‐12). IL‐23 induces differentiation of naive T cells into Th17. Activated Th17 cells overproduce IL‐17 and IL‐22. TNF‐α and IL‐17 activate keratinocytes, promote epidermal hyperplasia, recruit inflammatory cells, such as neutrophils, and induce antimicrobial peptide (AMP) production. IL‐12 produced by dendritic cells also induces Th1, and Th1 produce cytokines, including interferon (IFN)‐γ. This irregular immune response continues as TNF‐α activates dendritic cells. CXCL, chemokine (C‐X‐C motif) ligand.
The close relation between IL‐17 and psoriasis was reported. High levels of IL‐17 mRNA were detected in psoriatic lesional skin, but not in non‐lesional skin.25 In keratinocytes, IL‐17 enhanced the expression of IL‐6 and IL‐8, which are known as pro‐inflammatory cytokines and exacerbate psoriasis.26 In addition, topical application of imiquimod, a Toll‐like receptor (TLR)7/8 ligand and potent immune activator, induced psoriasis‐like dermatitis in mice together with the expression of IL‐17A and IL‐17F.27 Furthermore, both CsA and anti‐TNF‐α agents decreased the levels of IL‐17A, IFN‐γ, IL‐23p19 and chemokine (C‐C motif) ligand 20 in psoriatic lesions in conjunction with improvement of psoriatic eruptions, indicating that pro‐inflammatory cytokines, including IL‐17A, are involved in the development of psoriasis.26, 28-30 These findings suggest that the IL‐17 family plays an important role in psoriasis.
Interleukin‐22, a member of the IL‐10 cytokine family,31, 32 is closely related to psoriatic inflammation (Fig. 1). IL‐22 is mainly produced by Th17 cells. T22, which produces only IL‐22, has also been identified. The functional IL‐22 receptor is chiefly expressed on keratinocytes, and IL‐22 induces epidermal hyperplasia by enhancing keratinocyte proliferation. IL‐22 in the peripheral blood is also elevated in patients with psoriasis compared with healthy subjects.33 IL‐22 expression is increased in the psoriatic skin lesions and conversely decreased in association with remission by antipsoriatic therapy.33 These findings suggest that IL‐22 promotes keratinocyte proliferation and plays important roles in the pathology of psoriasis.
Dendritic cells, IL‐23 and TNF‐α
Interleukin‐23 was discovered in a study searching for members of the IL‐6 cytokine family.34 IL‐23 is a heterodimer composed of IL‐23p19 and IL‐12p40 (IL‐12/23p40) chains (Figs 1,2),35 and is produced by dendritic cells (DC), activated monocytes, macrophages, T cells and B cells.34, 36 IL‐23 binds to its heterodimeric receptor composed of IL‐12Rβ1 and IL‐23R subunits (Figs 1,2),35 which is expressed on memory T cells, natural killer T cells, monocytes and DC.37 IL‐23 regulates the development and maintenance of the Th17 population by promoting Th17 expansion. The role of IL‐23 in Th17 was demonstrated using mouse models of Th17‐related inflammation, autoimmune encephalomyelitis and collagen‐induced arthritis, which were substantially alleviated by a lack of IL‐23 receptors composed of IL‐23p19 and IL‐12p40 (IL‐12/23p40).38, 39
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Figure 2
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Interleukin (IL)‐23 and IL‐12 signaling pathway. IL‐23 and IL‐12 are similar heterodimeric cytokines secreted by activated dendritic cells (DC) in psoriatic lesions. IL‐23 consists of p40 and p19 subunits, but IL‐12 is composed of p40 and p35. IL‐23 receptor complex is composed of IL‐12Rβ1 and IL‐23R subunits. IL‐12 receptor complex consists of IL‐12Rβ1 and IL‐12Rβ2 instead of IL‐23R. Binding of IL‐23 to its receptor complex results in signal transducer and activator of transcription (STAT)3 phosphorylation through Jak2, which is located in the intracellular domain of the IL‐23R subunit. Phospho‐STAT3 proteins form homodimers. The homodimers are translocated into the nucleus and promote the Th17 response by inducing the expression of cytokines, including IL‐17A, IL‐17F IL‐22, and interferon (IFN)‐γ. In the IL‐12 signal transduction pathway, STAT4, but not STAT3, is phosphorylated. The T‐helper (Th)1 response is promoted by IFN‐γ induced by phospho‐STAT4 homodimers.
The role of IL‐23 in cutaneous inflammation has been investigated in both humans and mice. In humans, IL‐23p19 and IL‐12p40 (IL‐12/23p40) were shown to be overexpressed in psoriatic skin lesions, and most of the IL‐23p19 was produced by mature DC, monocytes and monocyte‐derived DC in the papillary dermis.40 In mice, IL‐23 was shown to mediate acanthosis and hyperkeratosis through the increased production of TNF‐α, IL‐12p40 (IL‐12/23p40), IL‐23p19 and IL‐20R2 (IL‐20 receptor subunit).41, 42 DC is the main source of IL‐23 in psoriatic skin lesions.
Dendritic cells are antigen‐presenting cells, and play a role in regulating differentiation of naive T cells to mature T cells. When activated, DC migrate from the skin into draining lymph nodes to present antigens and activate T‐cell responses.43 TNF and inducible nitric oxide synthase‐producing DC (Tip‐DC) are increased in psoriatic lesions,44 and produce large amounts of TNF‐α.
Tumor necrosis factor‐α plays a pivotal role in the pathogenesis of psoriasis (Fig. 1).45 TNF‐α activates the nuclear factor (NF)‐κB signal pathway, which affects cell survival, proliferation and anti‐apoptotic effects of lymphocytes and keratinocytes.46-48 In addition, TNF‐α stimulates keratinocytes to produce IL‐8, which leads to microabscess formation by enhancing neutrophil recruitment in psoriasis.49 TNF‐α induces Th17 to produce pro‐inflammatory cytokines through the NF‐κB pathway in psoriatic lesions, and blockade of the NF‐κB pathway results in a loss of IL‐17A production from CD4+ T cells.50 TNF‐α activity is elevated in psoriatic lesions, and TNF inhibitors cure the inflammatory condition in psoriatic lesions.51
Pathomechanism of Dyskeratosis
The epidermis is composed of a basal layer, spinous layer, granular layer and cornified layer. The transit time of keratinocytes from the basal layer to the spinous layer is reduced from approximately 13 days in the normal epidermis to only 48 h in psoriatic lesions.52 It was also reported that the cell cycle was shortened from 311 h in normal lesions to 36 h in basal keratinocytes of psoriatic lesions, indicating substantial acceleration of keratinocyte proliferation in psoriatic lesions.53 The pathomechanism underlying psoriasis is considered to involve the acceleration of cell proliferation and the rapid migration of keratinocytes from the basal layer to the granular layer. Keratinocyte proliferation is regulated by several molecules, such as cyclic antimicrobial peptide (AMP), protein kinase C, phospholipase C and transforming growth factor‐α.54
Keratin expression is also altered in the psoriatic epidermis. The differentiation‐specific keratins 1 and 10, which are chiefly expressed in the spinous layers are decreased, while keratins 6 and 16 are increased in the psoriatic epidermis.55 In addition, involucrin, transglutaminase 1 and keratin 17 are increased, whereas profilaggrin is decreased in psoriatic skin.55, 56 These findings show that the cytoskeletal protein profile is altered in the psoriatic epidermis. Psoriasis is characterized as a disorder of proliferation and differentiation in keratinocytes.
As described above, the psoriatic skin has very specific characteristics with regard to differentiation and proliferation of keratinocytes. The goal of psoriasis treatment is to control the differentiation and proliferation of keratinocytes. Treatments directly targeting keratinocytes seem to address these issues without direct risk of infection, unlike treatments that regulate the immune system. Retinoids and vitamin D are therapeutic methods that mainly target keratinocytes. Further analyses of the mechanisms underlying epidermal cell regulation are necessary.
Psoriasis and Antimicrobial Peptides
Antimicrobial peptides are found in a variety of organisms, including mammals, insects and plants. AMP are composed of 12–50 amino acids, and play roles in host defense via killing pathogens, such as bacteria, protozoa, fungi and some viruses.57, 58 Furthermore, they affect inflammatory responses by acting as chemotactic agents, angiogenic factors and regulators of cell proliferation. Various AMP, such as β‐defensins, S100 proteins and cathelicidin, are highly expressed in psoriatic lesions.57, 58 It was suggested that these AMP may play important roles in psoriasis.
The defensins, a family of cationic microbial peptides divided into three categories, namely defensins α, β and θ, contain six conserved cystein residues that form three pairs of intramolecular disulfide bonds.57, 59 The α‐defensins are further divided into six subtypes designated as human neutrophil peptides (HNP) 1–6, of which HNP 1–3 are present in the scales of psoriatic lesions.60 β‐Defensins are divided into four subtypes designated as human β‐defensins (hBD) 1–4. hBD 2–3 are expressed at high levels in psoriatic scales, and are induced by TNF‐α and IFN‐γ in keratinocytes.61, 62 In addition, hBD 2 is also induced by IL‐17A and IL‐22. The copy numbers of individual β‐defensins are associated with genetic influences of predisposition for psoriasis.63
The S100 proteins are a family of low molecular weight (9–13‐kDa) proteins characterized by the presence of two calcium binding sites in helix–loop–helix motifs.58, 64 Twenty‐one S100 proteins have been isolated to date, 13 of which are expressed in both the normal and psoriatic epidermis. S100A7 (psoriasin), S100A8 (calgranulin A), S100A9 (calgranulin B), S100A12 (calgranulin C) and S100A15 are abundantly expressed in psoriatic lesions, and some are elevated in the serum of psoriatic patients.59 Interestingly, keratinocytes, treated with combinations of IL‐22, IL‐17A and IL‐17F, showed induced expression of S100A9 with additively enhanced expression of S100A7 and S100A8.65 S100A7 may also have a chemotactic potential in psoriasis.66
Cathelicidins are also AMP, and one of the cathelicidins, LL‐37, is associated with the development of psoriasis.67 The LL‐37 highly expressed in the psoriatic epidermis may accelerate inflammation through its capacity to enable plasmacytoid DC to recognize self‐DNA via TLR9.68 In addition, type I IFN, which is expressed at high levels in psoriatic skin, is induced by stimulation with LL‐37 and DNA.69 These observations suggest the relation of the AMP with the pathomechanism of psoriasis.
Generalized Pustular Psoriasis and Related Genes
Studies of twins and families with psoriasis suggested that this disease is a multifactorial genodermatosis.70 The concordance rate of monozygotic twins is approximately 70% compared with approximately 20% for dizygotic twins.71 Furthermore, genome‐wide association studies with large cohorts have clarified the genetic aspects of psoriasis. Many genes involved in predisposition to psoriasis have been found, including HLA‐Cw6, ERAP1, IL12Bp40, IL23Ap19, IL4, IL13 and TNFAIP3.72, 73 However, these genes do not substantially predispose people to psoriasis. On the other hand, several genetic mutations have been shown to markedly influence the occurrence of generalized pustular psoriasis (GPP).
Generalized pustular psoriasis is a variant of psoriasis, and characterized by fever, general fatigue and dehydration, and is triggered by many factors, including systemic infection, pregnancy, hypocalcemia associated with hypothyroidism, and drugs.74 The accumulation of intraepidermal and subcorneal neutrophils in clusters called Kogoj's spongiform pustules suggests accelerated activation of neutrophils in GPP.
IL36RN
In 2011, deficiency of IL36RN was found in an autosomal recessive type of familial GPP, and IL36RN was noted as a causative gene for GPP in 2011.75 IL36RN encodes IL‐36 receptor antagonist (IL36Ra), which suppresses the function of IL‐36 (IL‐36α, IL‐36β and IL‐36γ) belonging to the IL‐1 family. All three IL‐36 subtypes are highly expressed in psoriatic lesions, and are robust inducers of neutrophil chemokines, including chemokine (C‐X‐C motif) ligand (CXCL)1 and CXCL8.76, 77 Deletion of the mouse ortholog of IL36RN, Il1f5, was also shown to lead to a skin phenotype similar to GPP in mice.78 Neutrophilic activation in GPP is likely developed by increased IL‐36 activity due to dysfunction of IL36Ra (Fig. 3).
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Figure 3
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Pathomechanism of familial generalized pustular psoriasis (GPP) with mutated interleukin (IL)‐36Ra. (a) IL‐36α, IL‐36β and IL‐36γ bind to the IL‐36 receptor and lead to inflammatory responses. (b) The IL‐36 receptor antagonist (IL‐36Ra) also binds to the IL‐36 receptor without biological activities, which blocks binding by IL‐36s. IL‐36Ra reduces the exacerbated inflammatory responses. (c) Mutated IL‐36Ra cannot antagonize IL‐36 signaling, and inflammatory responses are enhanced by exacerbated IL‐36 signaling.
CARD14
Caspase recruitment family member 14 (CARD14, also known as CARMA2) is a conserved scaffold protein that mediates TNF receptor‐associated factor 2 (TRAF2)‐dependent activation of NF‐κB signaling. Several gain‐of‐function mutations in CARD14, such as p.Gly117Ser, have been identified in GPP.79-83
AP1S3
AP1S3 encodes a subunit of AP‐1, which is a transcription factor that regulates the expression of keratins in keratinocytes. AP1S3 mutations were identified in GPP patients,84 and may induce IL‐1β, IL‐36 and CXCL8 expression through dysfunction of NF‐κB signaling.
Treatment Strategy for Psoriasis Based on its Pathogenesis
Retinoids
Retinoids, namely vitamin A and related compounds, have been used to treat eruptions in psoriasis since the early 1980s. Retinoids affect gene transcription via binding to two distinct families of nuclear receptors, retinoic acid receptors (RAR) and retinoid X receptors (RXR),85 which are ligand‐activated transcription factors that bind to retinoid hormone response elements in the promoter regions of target genes, including IL‐6.86 Retinoids improve the symptoms of psoriasis by regulating not only cell proliferation/differentiation but also inflammation. The pro‐inflammatory cytokines IL‐6 and migration inhibition factor‐related protein 8 are decreased through RAR binding.87
The third‐generation retinoid, tazarotene, has been approved for use in the USA and Europe as a therapeutic agent for psoriasis, which has fewer side‐effects than previous retinoid agents.88
Etretinate is the only retinoid approved by the health insurance system in Japan for the treatment of psoriasis. However, etretinate shows teratogenicity89 and accumulates in the body for a long period. Acitretin, a pharmacologically active derivative of etretinate, is used in other countries because it has a shorter elimination half‐life.90
Vitamin D
Vitamin D plays important roles in the maintenance of skin homeostasis. Photochemical cleavage of 7‐dehydrocholesterol to form vitamin D takes place in the skin and requires minimal exposure to ultraviolet B to generate physiological quantities of the product.91
Vitamin D binds to its receptor, inducing many events in the cell. The vitamin D receptor (VDR) is a phosphopeptide with a molecular weight of approximately 60 kD. VDR is a member of the nuclear receptor transcriptional factor superfamily, similar to RAR and RXR. The VDR acts preferentially as a heterodimer with the RXR on specific DNA sequences in the promoter regions of vitamin D target genes.
Vitamin D affects not only keratinocyte proliferation and differentiation but also inhibit immune response, improving symptoms of psoriatic patients.91 In psoriatic skin, vitamin D increases the expression of Bcl‐xL and induces apoptosis of keratinocytes.92
In addition, vitamin D possesses immunomodulatory activities. In vitro, vitamin D inhibits the production of IL‐8 and regulated and normal T‐cell expressed and secreted (RANTES) and upregulates expression of the receptor for the anti‐inflammatory cytokine, IL‐10, in keratinocytes.93, 94 Vitamin D also inhibits monocyte differentiation into DC95 and lymphocyte activation by promoting the release of IL‐2.96, 97
PDE4 inhibitor
Phosphodiesterase (PDE) degrades the intracellular phosphodiesterase bonds of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). PDE4 is an isoenzyme with predominant cAMP degradation activity, and is expressed in most immune cells, including lymphocytes, granulocytes and monocytes/macrophages, as well as epithelial cells.98 The intracellular second messenger, cAMP, inhibits the NF‐κB pathway directly or via phosphorylation of cAMP response element binding protein (CREB) (Fig. 4).99 As the NF‐κB pathway is activated in psoriasis, cAMP stabilization due to PDE4 inhibition alleviates inflammation of psoriasis by suppression of the NF‐κB signal.100 Apremilast, a selective PDE4 inhibitor, has been approved for the treatment of psoriasis.99, 101
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Figure 4
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Nuclear factor (NF)‐κB signaling pathway (canonical pathway) and suppressive function of cyclic adenosine monophosphate (cAMP). ① Tumor necrosis factor (TNF)‐α binds to TNF receptor (TNFR), leading to phosphorylation of IκK (IKK)β, which is one of the subunits of the IKK complex, leading to its activation. ② Activated IKK complex phosphorylates IκB, leading to ubiquitination of IκB and subsequent proteasomal degradation. Degradation of IκB allows translocation of NF‐κB dimers composed of p50 and p65 into the nucleus. ③ NF‐κB promotes the transcription of various genes by binding to specific sequence binding site and induces inflammatory responses. ④ cAMP prevents IκB degradation by blocking IKK complex. ⑤ cAMP prevents the degradation of IκB by also interfering with IκB ubiquitination. ⑥ cAMP induces transcription of IκB by upregulating cAMP response element binding protein (CREB) levels. ⑦ cAMP inhibits this NF‐κB pathway by elevating IκB levels at multiple points. Phosphodiesterase (PDE)4 degrades cAMP into 5′‐antimicrobial peptide (AMP), reducing inhibition of the NF‐κB signaling pathway by cAMP. ⑧ PDE4 inhibition results in elevation of cAMP levels in the cytoplasm, thus suppressing NF‐κB activities and inflammation responses. iNos, inducible nitric oxide synthase.
CsA
Cyclosporin A (CsA) was a key agent for the treatment of severe psoriasis until the development of biologics, and CsA is still an important medication for psoriasis.102 CsA improves psoriatic inflammation by inhibiting T‐cell activation. T‐cell receptor activation by antigen binding induces an increase in intracellular calcium level, which activates calcineurin by binding of calcium with calmodulin. Activated calcineurin dephosphorylates the cytoplasmic portion of the nuclear factor of activated T cells (NFATc), leading to translocation of NFATc into the nucleus and induction of transcription of IL‐2 and several other cytokines. CsA forms a complex with cyclophilins, thus blocking NFATc dephosphorylation, cytokine production and T‐cell infiltration.103
Cyclosporin A is highly effective, although it is associated with a number of side‐effects, including hypertension, nephrotoxicity and hepatotoxicity. In addition, CsA carries an increased risk of the development of lymphoproliferative disorders and other malignancies.104, 105 It is recommended that long‐term treatment with CsA is desirable until 2 years in Europe.105
Biologics
Therapies using biologics target major pathogenic cytokines involved in psoriasis, such as TNF‐α, IL‐23, and IL‐17 in the IL‐23/Th17 axis.104, 105 TNF‐α inhibitors were the first biologics used in psoriasis and showed good efficacy in this condition. Thereafter, IL‐12p40 (IL‐12/23p40) inhibitors were then applied to psoriasis.106 p40 is a subunit common to both IL‐12 and IL‐23, which inhibits the differentiation from naive T cells into Th1 and Th17 cells, because IL‐12 and IL‐23 are essential in the mechanisms of differentiation. Anti‐IL‐12p40 antibody suppresses the activities of both Th17 and Th1 through IL‐12 and IL‐23 pathways.107-110 IL‐17 inhibitors directly suppress the IL‐17 pathway, which is related to psoriasis. Therefore, the rates of patients attaining at least 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI)‐75 and PASI‐90 were extremely high in previous studies of other biologics, and the effect was expressed rapidly.107-112 Anti‐IL‐23p19 antibody formulation for clinical use is in the final stages of development, and it has also been reported to be very effective.113 For reference, the biologics approved in Japan are outlined in Table 1.
Table 1. Currently available biologics
Generic name Trade name Target Conformation
Infliximab Remicade TNF‐α Chimeric IgG1
Adalimumab Humira TNF‐α Human IgG1
Ustekinumab Stelara IL‐12/23 p40 Human IgG1/κ
Secukinumab Cosentyx IL‐17A Human IgG1
Ixekizumab Taltz IL‐17A Humanized IgG4
Brodalumab Lumicef IL‐17 receptor A Human IgG2
Guselkumab (PhaseIII) IL‐23 p19 Human IgG1/λ
Tildrakizumab (PhaseIII) IL‐23 p19 Humanized IgG1/κ
Risankizumab (PhaseIII) IL‐23 p19 Human IgG1
Ig, immunoglobulin; IL, interleukin; TNF, tumor necrosis factor.
Conclusion
The pathogenesis of psoriasis involves various cell types, including inflammatory cells and keratinocytes, as well as antimicrobial peptides. Additional basic studies regarding the pathogenesis will lead to the further development of therapeutic agents for psoriasis.Pathogenesis of psoriasis and development of treatment - Ogawa - 2018 - The Journal of Dermatology - Wiley Online Library
https://onlinelibrary.wiley.com/doi/full/10.1111/1346-8138.14139
Anti-allergic activity of glycyrrhizic acid on IgE-mediated allergic reaction by regulation of allergy-related immune cells
Glycyrrhizic acid (GA), the major bioactive triterpene glycoside of glycyrrhiza, has been shown to possess a wide range of pharmacological properties, including anti-inflammatory and anti-viral properties. However, few studies have examined the anti-allergic activity and exact mechanism of action of GA. In the present work, the anti-allergic activity and possible mechanisms of action of GA on an immunoglobulin (Ig) E-mediated allergic reaction has been studied using three models of allergic reaction in vivo and in vitro. Active systemic allergic reaction in Balb/c mice showed that GA can suppress the increased level of IL-4 to restore the immune balance of TH1/TH2 cells in a dose-dependent manner. Additionally, GA attenuated significantly the B cells producing allergen-specific IgE and IgG1 partly because of the low levels of TH2 cytokines. Both passive cutaneous anaphylaxis in vivo and an RBL-2H3 cell-based immunological assay in vitro indicated that GA acted as a "mast cell stabilizer", as it inhibited mast cell degranulation and decreased vascular permeability by inhibiting the expression of Orai1, STIM1 and TRPC1, which blocked extracellular Ca2+ influxes. The current study suggests that GA may serve as an effective anti-allergic agent derived from food for the prevention and treatment of IgE-mediated allergic reaction.https://pubmed.ncbi.nlm.nih.gov/28775294/
青蒿素抗过敏
https://pubmed.ncbi.nlm.nih.gov/28775294/
Lauric acid ameliorates lipopolysaccharide (LPS)-induced liver inflammation by mediating the TLR4/MyD88 pathway in Sprague Dawley (SD) rats
Lipopolysaccharide (LPS) is an endotoxin that leads to inflammation in many organs, including liver. It binds to pattern recognition receptors, that generally recognise pathogen expressed molecules to transduce signals that result in a multifaceted network of intracellular responses ending up in inflammation.
Aim
In this study, we used lauric acid (LA), a constituent abundantly found in coconut oil to determine its anti-inflammatory role in LPS-induced liver inflammation in Sprague Dawley (SD) rats.Method
Male SD rats were divided into five groups (n = 8), injected with LPS and thereafter treated with LA (50 and 100 mg/kg) or vehicle orally for 14 days. After fourteen days of LA treatment, all the groups were humanely killed to investigate biochemical parameters followed by pro-inflammatory cytokine markers; tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β. Moreover, liver tissues were harvested for histopathological studies and evaluation of targeted protein expression with western blot and localisation through immunohistochemistry (IHC).
Results
The study results showed that treatment of LA 50 and 100 mg/kg for 14 days were able to reduce the elevated level of pro-inflammatory cytokines, liver inflammation, and downregulated the expression of TLR4/NF-κB mediating proteins in liver tissues.
Conclusion
These findings suggest that treatment of LA has a protective role against LPS-induced liver inflammation in rats, thus, warrants further in-depth investigation through mechanistic approaches in different study models.https://www.sciencedirect.com/science/article/abs/pii/S0024320520315034
Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophages
Increased circulating free fatty acids in subjects with type 2 diabetes may contribute to activation of macrophages, and thus the development of atherosclerosis.In this study, we investigated the effect of the saturated fatty acids (SFA) palmitate, stearate, myristate and laurate, and the unsaturated fatty acid linoleate, on the production of proinflammatory cytokines in phorbol ester-differentiated THP-1 cells, a model of human macrophages. Palmitate induced secretion and mRNA expression of TNF-alpha, IL-8 and IL-1 beta, and enhanced lipopolysaccharide (LPS)-induced IL-1 beta secretion. Proinflammatory cytokine secretion was also induced by stearate, but not by the shorter chain SFA, myristate and laurate, or linoleate. Triacsin C abolished the palmitate-induced cytokine secretion, suggesting that palmitate activation to palmitoyl-CoA is required for its effect. Palmitate-induced cytokine secretion was decreased by knockdown of serine palmitoyltransferase and mimicked by C(2)-ceramide, indicating that ceramide is involved in palmitate-induced cytokine secretion. Palmitate phosphorylated p38 and JNK kinases, and blocking of these kinases with specific inhibitors diminished the palmitate-induced cytokine secretion. Palmitate also activated the AP-1 (c-Jun) transcription factor. Knockdown of MyD88 reduced the palmitate-induced IL-8, but not TNF-alpha or IL-1 beta secretion. In conclusion, our data suggest that the long-chain SFA induce proinflammatory cytokines in human macrophages via pathways involving de novo ceramide synthesis. This might contribute to the activation of macrophages in atherosclerotic plaques, especially in type 2 diabetes.https://pubmed.ncbi.nlm.nih.gov/21054880/
Palmitate and insulin synergistically induce IL-6 expression in human monocytes
Background: Insulin resistance is associated with a proinflammatory state that promotes the development of complications such as type 2 diabetes mellitus (T2DM) and atherosclerosis. The metabolic stimuli that initiate and propagate proinflammatory cytokine production and the cellular origin of proinflammatory cytokines in insulin resistance have not been fully elucidated. Circulating proinflammatory monocytes show signs of enhanced inflammation in obese, insulin resistant subjects and are thus a potential source of proinflammatory cytokine production. The specific, circulating metabolic factors that might stimulate monocyte inflammation in insulin resistant subjects are poorly characterized. We have examined whether saturated nonesterified fatty acids (NEFA) and insulin, which increase in concentration with developing insulin resistance, can trigger the production of interleukin (IL)-6 and tumor necrosis factor (TNF)-α in human monocytes.Methods: Messenger RNA and protein levels of the proinflammatory cytokines IL-6 and TNF-α were measured by quantitative real-time PCR (qRT-PCR) and Luminex bioassays. Student's t-test was used with a significance level of p < 0.05 to determine significance between treatment groups
Results: Esterification of palmitate with coenzyme A (CoA) was necessary, while β-oxidation and ceramide biosynthesis were not required, for the induction of IL-6 and TNF-α in THP-1 monocytes. Monocytes incubated with insulin and palmitate together produced more IL-6 mRNA and protein, and more TNF-α protein, compared to monocytes incubated with palmitate alone. Incubation of monocytes with insulin alone did not affect the production of IL-6 or TNF-α. Both PI3K-Akt and MEK/ERK signalling pathways are important for cytokine induction by palmitate. MEK/ERK signalling is necessary for synergistic induction of IL-6 by palmitate and insulin.
Conclusions: High levels of saturated NEFA, such as palmitate, when combined with hyperinsulinemia, may activate human monocytes to produce proinflammatory cytokines and support the development and propagation of the subacute, chronic inflammatory state that is characteristic of insulin resistance. Results with inhibitors of β-oxidation and ceramide biosynthesis pathways suggest that increased fatty acid flux through the glycerolipid biosynthesis pathway may be involved in promoting proinflammatory cytokine production in monocytes.https://pubmed.ncbi.nlm.nih.gov/21054880/
Palmitate, but not unsaturated fatty acids, induces the expression of interleukin-6 in human myotubes through proteasome-dependent activation of nuclear factor-kappaB - PubMed
https://pubmed.ncbi.nlm.nih.gov/15028733/
J Immunol. 2019 Jul 15;
Lactic Acid Inhibits Lipopolysaccharide-Induced Mast Cell Function by Limiting Glycolysis and ATP Availability
Sepsis has a well-studied inflammatory phase, with a less-understood secondary immunosuppressive phase. Elevated blood lactate and slow lactate clearance are associated with mortality; however, regulatory roles are unknown. We hypothesized that lactic acid (LA) contributes to the late phase and is not solely a consequence of bacterial infection. No studies have examined LA effects in sepsis models in vivo or a mechanism by which it suppresses LPS-induced activation in vitro. Because mast cells can be activated systemically and contribute to sepsis, we examined LA effects on the mast cell response to LPS. LA significantly suppressed LPS-induced cytokine production and NF-κB transcriptional activity in mouse bone marrow-derived mast cells and cytokine production in peritoneal mast cells. Suppression was MCT-1 dependent and reproducible with sodium lactate or formic acid. Further, LA significantly suppressed cytokine induction following LPS-induced endotoxemia in mice. Because glycolysis is linked to inflammation and LA is a byproduct of this process, we examined changes in glucose metabolism. LA treatment reduced glucose uptake and lactate export during LPS stimulation. LA effects were mimicked by glycolytic inhibitors and reversed by increasing ATP availability. These results indicate that glycolytic suppression and ATP production are necessary and sufficient for LA effects. Our work suggests that enhancing glycolysis and ATP production could improve immune function, counteracting LA suppressive effects in the immunosuppressive phase of sepsis.
Lactic Acid Inhibits Lipopolysaccharide-Induced Mast Cell Function by Limiting Glycolysis and ATP Availability - PubMed
https://pubmed.ncbi.nlm.nih.gov/31160535/
OCT 11, 2017,
Lactic Acid: No Longer an Inert and End-Product of Glycolysis
第四军医大学
For decades, lactic acid has been considered a dead-end product of glycolysis. Research in the last 20+ years has shown otherwise. Through its transporters (MCTs) and receptor (GPR81), lactic acid plays a key role in multiple cellular processes, including energy regulation, immune tolerance, memory formation, wound healing, ischemic tissue injury, and cancer growth and metastasis. We summarize key findings of lactic acid signaling, functions, and many remaining questions.
Lactic Acid: No Longer an Inert and End-Product of Glycolysis | Physiology
https://journals.physiology.org/doi/full/10.1152/physiol.00016.2017
Immune cell metabolism in autoimmunity
Glycolysis
Glycolysis refers to the metabolic pathway by which glucose is metabolized. The first common phase of glycolysis is the production of pyruvate. Pyruvate is then either oxidized in the Krebs cycle, leading to the production of up to 38 molecules of ATP per molecule of glucose, or reduced into lactate in either hypoxic conditions or when metabolite intermediates are needed over ATP production, which in this case is limited to two molecules. Glycolysis commonly refers to this lactate end‐point branch of glycolysis, while the other is referred to as glucose oxidative or mitochondrial metabolism. Activation of CD4+ T cells from lupus‐prone mice and SLE patients occurs with high levels of oxygen consumption and oxidation 31, 33. Lupus T cells also display a high level of glycolysis 31, with oxidation representing a major part of glucose utilization 32. Glucose transporters provide the ‘primary first step’ of glycolysis by importing glucose into the cell. The major glucose transporter expressed by T cells is Glut1, which is significantly up‐regulated upon T cell receptor and co‐stimulator CD28 signaling 34. Over‐expression of Glut1 in mice led to the accumulation of activated CD4+ T cells, the production of autoantibodies and a modest immune complex deposition in the glomeruli of aged mice 35. Furthermore, these mice showed increased Tfh and GC B cell numbers, with elevated IL‐21 and immunoglobulin (Ig)A production 13. The combination of 2‐deoxy‐D‐glucose (2DG), a glycolysis inhibitor, and metformin, which inhibits complex I of the mitochondrial electron transport chain 36, reversed lupus pathogenesis in mice 31. While treatment with either metformin or 2DG alone could prevent the development of the disease 32, these results indicate that targeting cellular metabolism could be a potential therapy for lupus and other autoimmune diseases 37. Among the subsets of T cells, Tfh cells from lupus mice are highly glycolytic (Fig. 1), and their expansion as well as that of GC B cells was abrogated by 2DG treatment 26. This glycolytic requirement is restricted to autoreactive Tfh cells, as Tfh cells induced by immunization with a nominal antigen or by infection with influenza virus were not affected by 2DG 26. This suggests that the metabolic requirements of autoreactive CD4+ T cells are unique, which may provide a window of opportunity for their selective elimination. The expansion of Tfh cells was also kept in check by 2DG in the K/BXN model of RA, which indicated that the high glucose requirement of autoreactive Tfh cells is not model‐dependent 38. 2DG‐treated K/BXN mice also showed a reduced disease severity, in association with a decreased T and B cell metabolism and a reduced activation of both adaptive and innate immune cells 38. In the same RA model, reducing glycolysis by targeting hexokinase (HK) showed beneficial effects by decreasing the activation of fibroblast‐like synoviocytes 39. Contrary to murine RA T cells and synoviocytes, glycolysis is reduced in the CD4+ T cells from RA patients, which develop a hyper‐reduced state due to an over‐active pentose phosphate pathway (PPP) 40. The pathogenicity of these T cells can be reduced by diverting the glucose flux away from PPP 41 or with oxidative agents 42. Lactate accumulation has been reported in the synovia of RA patients, which may be secondary to the hypoxic conditions in the inflamed joint. The excess is responsible for the ‘entrapment’ of CD4+ and CD8+ T cells. The expression of lactate transporters on these cells correlates with the clinical T cell score in the synovia of RA patients. Lactate directly inhibits CD4+ T cell motility by interfering with glycolysis activated upon engagement of the chemokine receptor C‐X‐C motif chemokine receptor 3 (CXCR3) with C‐X‐C motif chemokine ligand 10 (CXCL10) 43. These results suggest that blocking lactate production in the RA joint may decrease T cell infiltrates and present therapeutic benefits. Pyruvate dehydrogenase (PDH) promotes the oxidative phosphorylation of pyruvate over the lactate glycolytic pathway. Pyruvate dehydrogenase phosphatase catalytic subunit 2 (PDP2) converts the inactive PDH to its active form. PDP2 expression was decreased in memory Th17 cells from patients with SLE and forced expression of PDP2 in CD4+ T cells from lupus‐prone MRL/lpr mice and patients with SLE‐suppressed Th17 differentiation. This may be due at least partly to the direct control of energy production by the transcription factor‐inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) at the PDH metabolism bifurcation level 44. These results are consistent with the glycolytic requirements of Th17 cells 45 and the expansion of Th17 cells in SLE patients 15. Finally, dimethyl fumarate, a derivative of the Krebs cycle intermediate fumarate that inactivates glyceraldehyde 3‐phosphate dehydrogenase (GAPDH) and therefore inhibits both branches of glycolysis, altered the differentiation and function of Th1 and Th17 cells, attenuating disease in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis 46, stressing again the potentials of glucose metabolic inhibitors to target pathogenic autoreactive T cells. HIF1α, a transcription factor that controls the cellular response to hypoxia, activates the glycolytic pathway and, as such, promotes inflammation 47. HIF1α expression is required for the differentiation of Th17 cells 45, a T cell subset expanded in many autoimmune and inflammatory diseases. Mice with a B cell‐specific deletion of HIF1α have reduced numbers of IL‐10‐producing B cells, which exacerbate collagen‐induced arthritis and EAE 48. HIF1α‐inhibitor echinomycin reduced Th1 and Th17 responses, and attenuated a mouse model of acute graft‐versus‐host disease 49. Moreover, hypoxia induced HIF1α expression as well as signal transducer and activator of transcription (STAT)‐1 and STAT‐3 activation in human RA‐fibroblast‐like synoviocytes (FLS). STAT‐3 knock‐down inhibited HIF1α expression and the hypoxia‐induced cell invasion, migration and cytokine production, indicating a functional link between HIF1α and STAT‐3 in the regulation of proinflammatory mechanisms in RA 50. Prolyl hydroxylase domain (PHD) are enzymes that regulate HIFα levels by promoting its degradation. PHD‐2 is the major hydroxylase regulating HIF levels and the expression of angiogenic genes in RA‐FLS, illustrating the major role played by hypoxia in the RA joint 51. Finally, knocking down HIF1α in myeloid cells ameliorated induced colitis 52. Taken together, targeting glycolysis directly and indirectly may present promising therapeutic venues to treat autoimmune diseases; however, detailed disease‐specific analyses of preclinical models are necessary to understand the cellular targets and specific pathways in glucose flux that are responsible for pathogenesis.
Immune cell metabolism in autoimmunity - Teng - 2019 - Clinical & Experimental Immunology - Wiley Online Library
https://onlinelibrary.wiley.com/doi/full/10.1111/cei.13277
Ascorbic acid, a well-known ROS scavenger, was found to sensitize imatinib-resistant cancer cells by decreasing the levels of the NRF2/ARE complex, hence reducing the expression of Glutamate-Cysteine Ligase Catalytic Subunit and dropping GSH levels
Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development
https://www.hindawi.com/journals/omcl/2019/9372182/
Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development
https://www.hindawi.com/journals/omcl/2019/9372182/
Nrf2 Promotes Keratinocyte Proliferation in Psoriasis through Up-Regulation of Keratin 6, Keratin 16, and Keratin 17
Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation of epidermis. Although hyperproliferation-associated keratins K6, K16, and K17 are considered to be the hallmarks of psoriasis, the molecular basis underlying the overexpression of these keratins remains unclear. Nrf2 regulates cell proliferation. Therefore, we investigated whether Nrf2 regulates keratinocyte proliferation via promoting expression of K6, K16, and K17 in psoriasis. We initially found that psoriatic epidermis exhibited elevated expression of Nrf2. Furthermore, Nrf2 promoted expression of K6, K16, and K17 in both HaCaT cells and primary human keratinocytes by binding to the ARE domains located in the promoter of these genes. Additionally, upon stimulation with IL-17 or IL-22, Nrf2 translocated to the nucleus and initiated expression of targeted keratins. In mice of imiquimod-induced psoriasis-like dermatitis, topical application of Nrf2 small interfering RNA alleviated the epidermal hyperplasia with reduced expression of these keratins. More importantly, Nrf2 promoted the proliferation of human keratinocytes through up-regulation of K6, K16, or K17. These data suggested that inflammatory cytokines promoted Nrf2 nuclear translocation in psoriatic epidermis, which led to elevated expression of K6, K16, and K17, thus promoting keratinocyte proliferation and contributing to the pathogenesis of psoriasis.
Nrf2 Promotes Keratinocyte Proliferation in Psoriasis ...
https://www.jidonline.org/article/S0022-202X(17)31561-0/fulltext
Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation of epidermis. Although hyperproliferation-associated keratins K6, K16, and K17 are considered to be the hallmarks of psoriasis, the molecular basis underlying the overexpression of these keratins remains unclear. Nrf2 regulates cell proliferation.
Cited by: 57
Publish Year: 2017
Author: Luting Yang, Xueli Fan, Tingting Cui, Erle Dang
The role of quercetin and vitamin C in Nrf2‑dependent oxidative stress production in breast cancer cells
The role of quercetin and vitamin C in Nrf2‑dependent oxidative stress production in breast cancer cells
https://www.spandidos-publications.com/ol/13/3/1965
Psoriasiform dermatitis is driven by IL-36–mediated DC-keratinocyte crosstalk
Published October 15, 2012 - More info
Abstract
Psoriasis is a chronic inflammatory disorder of the skin affecting approximately 2% of the world’s population. Accumulating evidence has revealed that the IL-23/IL-17/IL-22 pathway is key for development of skin immunopathology. However, the role of keratinocytes and their crosstalk with immune cells at the onset of disease remains poorly understood. Here, we show that IL-36R–deficient (Il36r–/–) mice were protected from imiquimod-induced expansion of dermal IL-17–producing γδ T cells and psoriasiform dermatitis. Furthermore, IL-36R antagonist-deficient (Il36rn–/–) mice showed exacerbated pathology. TLR7 ligation on DCs induced IL-36–mediated crosstalk with keratinocytes and dermal mesenchymal cells that was crucial for control of the pathological IL-23/IL-17/IL-22 axis and disease development. Notably, mice lacking IL-23, IL-17, or IL-22 were less well protected from disease compared with Il36r–/– mice, indicating an additional distinct activity of IL-36 beyond induction of the pathological IL-23 axis. Moreover, while the absence of IL-1R1 prevented neutrophil infiltration, it did not protect from acanthosis and hyperkeratosis, demonstrating that neutrophils are dispensable for disease manifestation. These results highlight a central and unique IL-1–independent role for IL-36 in control of the IL-23/IL-17/IL-22 pathway and development of psoriasiform dermatitis.JCI - Psoriasiform dermatitis is driven by IL-36–mediated DC-keratinocyte crosstalk
https://www.jci.org/articles/view/63451