Jürgensen Henrik J, Silva Lakmali M, Krigslund Oliver, van Putten Sander, Madsen Daniel H, Behrendt Niels, Engelholm Lars H, Bugge Thomas H
Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA.
Finsen Laboratory, Rigshospitalet/BRIC, University of Copenhagen, Ole Maaloesvej 5, DK-2200 Copenhagen N, Denmark.
Matrix Biol Plus. 2019 Mar 19;1:100003. doi: 10.1016/j.mbplus.2019.03.002. eCollection 2019 Feb.
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 , 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 CCR2 macrophages 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.
巨噬细胞的可塑性、细胞起源和表型异质性，对于研究这种关键免疫细胞在发育、稳态以及组织重塑/修复过程中的生物学特性而言，始终是一项挑战。因此，在这些背景下已描述了无数种巨噬细胞亚型。为便于识别功能性巨噬细胞亚型，我们在此采用了一种基于流式细胞术的检测方法，该方法能够对参与细胞外基质（ECM）降解的巨噬细胞进行详细的表型分析。通过该检测方法在重塑真皮中鉴定出的五种巨噬细胞亚型中，胶原降解主要由Ly6C⁺CCR2⁻和Ly6C⁻CCR2⁺巨噬细胞通过甘露糖受体依赖性胶原内吞作用来执行，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信号轴对胶原和纤维蛋白降解均至关重要，而胶原降解独立于IL-4Ra信号。此外，细胞因子GM-CSF选择性地增强了Ly6C⁺CCR2⁻巨噬细胞的胶原降解。本研究揭示了参与ECM周转的不同巨噬细胞亚群，并确定了CCL2和GM-CSF炎性细胞因子与伤口愈合相关的新功能。
