Complement Deficiency Promotes Cutaneous Wound Healing in Mice

Abstract

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. Here 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 to 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.

Complement in disease: a defence system turning offensive

“…Given their simultaneous activation at the site of injury, crosstalk between complement, coagulation pathways and TLRs might be particularly relevant in this setting 89 . Interestingly, findings from animal studies suggest that complement might also influence the repair process after trauma by inducing osteoclastogenesis and contributing to wound healing 89,90 . A 2015 study of spinal cord injury in mice showed that early inhibition of C5aR1 during the acute phase of injury improved clinical outcomes, whereas extended blockade during the chronic phase of injury did not, indicating dual roles for complement in inflammation and repair 91 .…”

Novel mechanisms and functions of complement

“…C3, which is hyperexpressed in human psoriatic epidermis, is also aberrantly upregulated in a mouse psoriasis model by calprotectin (S100A8-S100A9 complex) and drives the disease phenotype 37 . Complement also influences cutaneous wound healing, where C3 –/– and C5ar1 –/– mice exhibit an accelerated healing phenotype, suggesting that recruitment and activation of inflammatory cells to the wound might delay the healing process 38 .…”

Complement Activation and STAT4 Expression Are Associated with Early Inflammation in Diabetic Wounds

“…Additionally, the healing kinetics of the two groups were statistically similar until day 8[39]. The complement cascade is rapidly activated in response to wounding[40], and it has been shown that mice deficient in C3 or C5 displayed accelerated wound healing in the early stages (days1-3) of normal wound healing[41]. Therefore, the critical aspect in determining the efficacy of complement as a therapeutic target was to evaluate the kinetics of C5 and C3a in the initial 48 hours post-wounding in both normal and diabetic wounds, and if inhibition of C1 could reestablish levels seen in normal wound healing.…”

“…Complement can be activated by the classical, lectin or alternative pathways, but most commonly activation is triggered by the classical or lectin pathways with the alternative pathway functioning as a positive-feedback loop[15]. Complement activation occurs in skin wounds and has been shown to contribute to altered wound healing in several models including burn wounds[16–19]. It is likely that complement plays multiple roles in a wound including innate immune protection against infection as well as potentially inhibiting healing if activation is dysregulated.…”