Rafail Stavros, Kourtzelis Ioannis, Foukas Periklis G, Markiewski Maciej M, DeAngelis Robert A, Guariento Mara, Ricklin Daniel, Grice Elizabeth A, Lambris John D
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Abteilung für Klinische Pathobiochemie, Medizinische Fakultät, Technische Universität Dresden, 01307 Dresden, Germany;
J Immunol. 2015 Feb 1;194(3):1285-91. doi: 10.4049/jimmunol.1402354. Epub 2014 Dec 29.
Wound healing is a complex homeostatic response to injury that engages numerous cellular activities, processes, and cell-to-cell interactions. The complement system, an intricate network of proteins with important roles in immune surveillance and homeostasis, has been implicated in many physiological processes; however, its role in wound healing remains largely unexplored. In this study, we employ a murine model of excisional cutaneous wound healing and show that C3(-/-) mice exhibit accelerated early stages of wound healing. Reconstitution of C3(-/-) mice with serum from C3(+/+) mice or purified human C3 abrogated the accelerated wound-healing phenotype. Wound histology of C3(-/-) mice revealed a reduction in inflammatory infiltrate compared with C3(+/+) mice. C3 deficiency also resulted in increased accumulation of mast cells and advanced angiogenesis. We further show that mice deficient in the downstream complement effector C5 exhibit a similar wound-healing phenotype, which is recapitulated in C5aR1(-/-) mice, but not C3aR(-/-) or C5aR2(-/-) mice. Taken together, these data suggest that C5a signaling through C5aR may in part play a pivotal role in recruitment and activation of inflammatory cells to the wound environment, which in turn could delay the early stages of cutaneous wound healing. These findings also suggest a previously underappreciated role for complement in wound healing, and may have therapeutic implications for conditions of delayed wound healing.
伤口愈合是机体对损伤的一种复杂的稳态反应，涉及众多细胞活动、过程以及细胞间相互作用。补体系统是一个由蛋白质构成的复杂网络，在免疫监视和稳态中发挥重要作用，已被证实参与许多生理过程；然而，其在伤口愈合中的作用仍 largely 未被探索。在本研究中，我们采用了切除性皮肤伤口愈合的小鼠模型，结果显示 C3(-/-)小鼠伤口愈合的早期阶段加速。用 C3(+/+)小鼠的血清或纯化的人 C3 重建 C3(-/-)小鼠可消除伤口愈合加速的表型。与 C3(+/+)小鼠相比，C3(-/-)小鼠的伤口组织学显示炎症浸润减少。C3 缺乏还导致肥大细胞积累增加和血管生成提前。我们进一步表明，下游补体效应因子 C5 缺陷的小鼠表现出类似的伤口愈合表型，这种表型在 C5aR1(-/-)小鼠中重现，但在 C3aR(-/-)或 C5aR2(-/-)小鼠中未出现。综上所述，这些数据表明通过 C5aR 的 C5a 信号传导可能部分在炎症细胞募集和激活至伤口环境中起关键作用，进而可能延迟皮肤伤口愈合的早期阶段。这些发现还提示补体在伤口愈合中存在先前未被充分认识的作用，并且可能对伤口愈合延迟的情况具有治疗意义。
