CCL2/MCP-1 signaling drives extracellular matrix turnover by diverse macrophage subsets.
CCL2/MCP-1 signaling drives extracellular matrix turnover by diverse macrophage subsets.
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DOI：
10.1016/j.mbplus.2019.03.002
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发表时间：
2019-03
影响因子：
--
通讯作者：
Bugge TH
中科院分区：
文献类型：
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作者：
Jürgensen HJ;Silva LM;Krigslund O;van Putten S;Madsen DH;Behrendt N;Engelholm LH;Bugge TH
巨噬细胞的可塑性、细胞起源和表型异质性是解决这一关键免疫细胞在发育、稳态和组织重塑/修复中的生物学研究的永恒挑战。因此，在这些背景下描述了无数的巨噬细胞亚型。为了促进体内功能性巨噬细胞亚型的鉴定，我们在这里使用了基于流式细胞术的测定，该测定可以对参与细胞外基质（ECM）降解的巨噬细胞进行详细的表型分析。在使用该测定在重塑真皮中鉴定的五种巨噬细胞亚型中，胶原蛋白降解主要由 Ly6C−CCR2+ 和 Ly6C−CCR2low 巨噬细胞通过甘露糖受体依赖性胶原内吞作用执行，而 Ly6C+CCR2+ 巨噬细胞是主要的纤维蛋白内吞细胞。出乎意料的是，CCL2/MCP1-CCR2 信号传导轴对于胶原蛋白和纤维蛋白降解都至关重要，而胶原蛋白降解与 IL-4Ra 信号传导无关。此外，细胞因子 GM-CSF 选择性增强 Ly6C+CCR2+ 巨噬细胞对胶原蛋白的降解。这项研究揭示了参与 ECM 更新的巨噬细胞的不同亚群，并确定了 CCL2 和 GM-CSF 炎症细胞因子与伤口愈合相关的新功能。表型多样的真皮巨噬细胞亚群承担细胞外基质 C-C 基序趋化因子配体 2 (CCL2) 信号的降解，对于巨噬细胞介导的胶原蛋白和纤维蛋白内吞作用至关重要。粒细胞巨噬细胞集落刺激因子 (GM-CSF) 和白介素 (IL)-13 刺激胶原蛋白内吞作用。伤口愈合相关的 IL4-IL4 受体 a (IL4Ra) 信号对于巨噬细胞的胶原蛋白内吞作用是可有可无的。甘露糖受体是常驻真皮巨噬细胞利用的主要内吞胶原蛋白受体。
Macrophage plasticity, cellular origin, and phenotypic heterogeneity are perpetual challenges for studies addressing the biology of this pivotal immune cell in development, homeostasis, and tissue remodeling/repair. Consequently, a myriad of macrophage subtypes has been described in these contexts. To facilitate the identification of functional macrophage subtypes in vivo, here we used a flow cytometry-based assay that allows for detailed phenotyping of macrophages engaged in extracellular matrix (ECM) degradation. Of the five macrophage subtypes identified in the remodeling dermis by using this assay, collagen degradation was primarily executed by Ly6C−CCR2+ and Ly6C−CCR2low macrophages via mannose receptor-dependent collagen endocytosis, while Ly6C+CCR2+ macrophages were the dominant fibrin-endocytosing cells. Unexpectedly, the CCL2/MCP1-CCR2 signaling axis was critical for both collagen and fibrin degradation, while collagen degradation was independent of IL-4Ra signaling. Furthermore, the cytokine GM-CSF selectively enhanced collagen degradation by Ly6C+CCR2+ macrophages. This study reveals distinct subsets of macrophages engaged in ECM turnover and identifies novel wound healing-associated functions for CCL2 and GM-CSF inflammatory cytokines. Phenotypically diverse subsets of dermal macrophages undertake the degradation of extracellular matrix C-C motif chemokine Ligand 2 (CCL2) signaling is critical for macrophage-mediated endocytosis of collagen and fibrin. Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and Interleukin (IL)-13 stimulate collagen endocytosis. The wound healing-associated IL4-IL4 Receptor a (IL4Ra) signaling is dispensable for collagen endocytosis by macrophages. The mannose receptor is the principal endocytic collagen receptor utilized by resident dermal macrophages.