FADD- and RIPK3-mediated cell death ensures timely clearance of wound macrophages and promotes wound healing

Abstract

Cells of the monocyte/macrophage lineage are an integral component of the body's innate ability to restore tissue function after injury. In parallel to mounting an inflammatory response, clearance of monocytes/macrophages from the wound site is critical to re-establish tissue functionality and integrity during the course of healing. The role of regulated cell death in macrophage clearance from damaged tissue and its implications for the outcome of the healing response is little understood. Here, we explored the role of macrophage-specific FADD-mediated cell death on Ripk3-/- background in a mechanical skin injury model in mice. We found that combined inhibition of RIPK3-mediated necroptosis and FADD-caspase-8-mediated apoptosis in macrophages profoundly delayed wound healing. Importantly, RIPK3 deficiency alone did not considerably alter the wound healing process and macrophage population dynamics, arguing that inhibition of FADD-caspase-8-dependent death of macrophages is primarily responsible for the delayed wound closure. Notably, TNF blockade reversed the accumulation of Ly6Chigh macrophages induced by combined deficiency of FADD and RIPK3, indicating a critical dual role of TNF-mediated pro-survival and cell death signalling, particularly in this highly pro-inflammatory macrophage subset. Our findings reveal a previously uncharacterized cross-talk of inflammatory and cell death signalling in macrophages in regulating repair processes in the skin.

Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair

“…To further validate the role of cFLIP cleavage in protecting tissues from cell death–induced damage, we used a model of mouse full-thickness excisional skin injury. Because Caspase-8 was reported to play a crucial role in the wound healing response ( 45 ) and it was very recently shown that wound healing is a TNF- and cell death–dependent process ( 46 ), we wondered whether Caspase-8–mediated cFLIP cleavage could contribute to wound closure. The wound closure is characterized by the formation of the granulation tissue in the damaged area that is composed of different cell types whose concerted action promotes wound closure ( Fig.…”