AKT3 deficiency in M2 macrophages impairs cutaneous wound healing by disrupting tissue remodeling

Abstract

AKT signaling and M2 macrophage-guided tissue repair are key factors in cutaneous wound healing. A delay in this process threatens human health worldwide. However, the role of AKT3 in delayed cutaneous wound healing is largely unknown. In this study, histological staining and transcriptomics demonstrated that prolonged tissue remodeling delayed wound healing. This delay was accompanied by defects in AKT3, collagen alpha-1(I) chain (COL1A1), and collagen alpha-1(XI) chain (COL11A1) expression and AKT signaling. The defect in AKT3 expression was M2 macrophage-specific, and decreased AKT3 protein levels were observed in CD68/CD206positive macrophages from delayed wound tissue. Downregulation of AKT3 in M2 macrophages did not influence cell polarization but impaired collagen organization by inhibiting COL1A1 and COL11A1 expression in human skin fibroblasts (HSFs). Moreover, a co-culture model revealed that the downregulation of AKT3 in the human monocytic cell line (THP-1)-derived M2 macrophages impaired HSF proliferation and migration. Finally, cutaneous wound healing in AKT3-/mice was much slower than that of AKT3 +/+ mice, and F4/80 macrophages from the AKT3-/mice had an impaired ability to promote wound healing. Thus, the downregulation of AKT3 in M2 macrophages prolonged tissue remodeling and delayed cutaneous wound healing.

Single-Cell RNA Profiling of Human Skin Reveals Age-Related Loss of Dermal Sheath Cells and Their Contribution to a Juvenile Phenotype

“…Col11a1 expression is also highly increased in the neonatal mouse dermis and in mouse dermis that has been reprogrammed to a neonatal stage by epidermal beta catenin activation (Collins et al, 2011). Furthermore, COL11A1 is upregulated upon injection of hyaluronic acid-based dermal fillers (Huth et al, 2020) and downregulation of Col11a1 is associated with delayed wound healing (Gu et al, 2020). These observations might be attributed to our finding that COL11A1 increases the differentiation capacity.…”

Macrophage Related Chronic Inflammation in Non-Healing Wounds

“…In the remodeling phase, the myofibroblasts undergo apoptosis and newly formed granulation tissues are reorganized, and then lead to tissue homeostasis (7)(8)(9)(10)(11). However, interruptions or defects in these delicate phases may lead to a nonhealing wound state (6,12).…”

AXL-TBK1 driven nuclear AKT3 promotes metastasis

“…In fact, it has been reported that 7-DHC, a cholesterol precursor, regulates type I interferon production via AKT3 activation, where AKT3 directly binds and phosphorylates IRF3 on S385 (64). Additionally, AKT3 (pS473) in macrophages has been shown to promote migration, proliferation, wound healing, and collagen organization (65). Interestingly, a recent study showed that AKT3 phosphorylated RNA processing proteins that regulate the alternative splicing of fibroblast growth factor receptors (FGFR), consistent with an importance of nuclear targeting of AKT3 in EMT maintenance (21).…”