通过缺氧调节人巨噬细胞M1-M2极化平衡和在髓样细胞上表达的触发受体(TREM-1)

Regulation of Human Macrophage M1–M2 Polarization Balance by Hypoxia and the Triggering Receptor Expressed on Myeloid Cells-1 

　

摘要：

巨噬细胞（Mf）是组织驻留的专业吞噬细胞的异质群体，并且是炎症、感染和肿瘤生长部位的白细胞浸润的主要成分。

它们可以响应环境因素进行不同形式的激活，极化为专门的功能子集。

病理环境的共同标志是缺氧。缺氧对人体Mf极化的影响尚未完全确定。

本研究的目的是阐明体内病变组织常见的缺氧环境对Mf极化为经典激活（促炎症M1)和替代性激活（抗炎症M2）能力的影响。

我们提供的数据表明，缺氧通过降低T细胞共刺激分子和趋化因子归巢受体的表达以及典型经典激活的促炎性Th1引发细胞因子的表达来阻碍Mf极化向M1表型，同时促进它们获得表型和分泌特征的替代激活。此外，我们确定在骨髓细胞（TREM）-1（Ig样免疫调节受体家族的成员）中表达的触发受体，作为Mf中的缺氧诱导基因，并证明它与激动剂Ab的结合逆转了缺氧的M2极化作用，赋予M1表型的Mf。最后，我们提供证据表明Mf渗透受幼年特发性关节炎影响的儿童发炎的缺氧关节表达高表面水平的TREM-1与主要的M1极化相关，并提示该分子在缺氧滑膜环境中驱动M1促炎重编程的潜力。 。

 

Regulation of Human Macrophage M1–M2 Polarization Balance by Hypoxia and the Triggering Receptor Expressed on Myeloid Cells-1

Federica Raggi,1 Simone Pelassa,1 Daniele Pierobon,2 Federica Penco,3 Marco Gattorno,3

Laboratory of Molecular Biology, Giannina Gaslini Institute, Genoa, Italy

Abstract

Macrophages (Mf) are a heterogeneous population of tissue-resident professional phagocytes and a major component of the leukocyte infiltrate at sites of inflammation, infection, and tumor growth.

They can undergo diverse forms of activation in response to environmental factors, polarizing into specialized functional subsets.

A common hallmark of the pathologic environment is represented by hypoxia. The impact of hypoxia on human Mf polarization has not been fully established. The objective of this study was to elucidate the effects of a hypoxic environment reflecting that occurring in vivo in diseased tissues on the ability of human Mf to polarize into classically activated (proinflammatory M1) and alternatively activated (anti-inflammatory M2) subsets.

We present data showing that hypoxia hinders Mf polarization toward the M1 phenotype by decreasing the expression of T cell costimulatory molecules and chemokine homing receptors and the production of proinflammatory, Th1-priming cytokines typical of classical activation, while promoting their acquisition of phenotypic and secretory features of alternative activation. Furthermore, we identify the triggering receptor expressed on myeloid cells (TREM)-1, a member of the Ig-like immunoregulatory receptor family, as a hypoxia-inducible gene in Mf and demonstrate that its engagement by an agonist Ab reverses the M2-polarizing effect of hypoxia imparting a M1-skewed phenotype to Mf. Finally, we provide evidence that Mf infiltrating the inflamed hypoxic joints of children affected by oligoarticular juvenile idiopatic arthritis express high surface levels of TREM-1 associated with predominant M1 polarization and suggest the potential of this molecule in driving M1 proinflammatory reprogramming in the hypoxic synovial environment.

 

Front Immunol. 2017; 8: 1097.

Published online 2017 Sep 7. doi:  10.3389/fimmu.2017.01097

PMCID: PMC5594076

PMID: 28936211

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594076/