MLKL are involved in the regulation of skin wound healing and the interplay between macrophages and myofibroblasts

Abstract

The pseudokinase mixed lineage kinase domain-like protein (MLKL) acts as a crucial effector in the necroptosis pathway. It is widely recognized that MLKL-dependent necrosis is closely related to inflammation in wound healing, which contributes to detrimental pathologies. In present study, transcriptome sequencing data indicate sustained overexpression of MLKL throughout the wound healing process, extending beyond the early inflammation phase. In vivo experiments clearly demonstrate that MLKL deficiency delays skin wound healing, as evidenced by morphological observations and pathological characteristics. MLKL deficiency impairs the synthesis of inflammatory factors (IL-6, TNF-α, and PGE₂) and tissue repair-related molecules (EGF, VEGF, ERα, and MMP-9) at the wound site, potentially leading to delayed wound closure. Furthermore, we have identified the roles of MLKL and PGE₂ in the interaction between macrophages (both classically activated and alternatively activated) and myofibroblasts, an interaction essential at each stage of wound healing. Our findings suggest that MLKL's involvement in wound healing may not solely rely on necrosis-induced inflammatory responses during the early stages but also contributes to other activities in tissue regeneration.