Myeloid cell-specific sirtuin 6 deficiency delays wound healing in mice by modulating inflammation and macrophage...

Area of Science:

• Immunology
• Molecular Biology
• Dermatology

Background:

• Sirtuin 6 (Sirt6) in myeloid cells is critical for M1 macrophage polarization and chemotaxis.
• Macrophages are key players in wound repair, exhibiting significant heterogeneity.
• Sirt6 deficiency in myeloid cells may impede skin wound healing by altering macrophage phenotypes.

Purpose of the Study:

• To investigate the role of myeloid cell-specific Sirtuin 6 (Sirt6) deficiency in skin wound closure.
• To determine the impact of Sirt6 deficiency on macrophage polarization and function during wound healing.
• To elucidate the underlying molecular mechanisms of impaired wound healing in Sirt6-deficient mice.

Main Methods:

• Generation of myeloid cell-specific Sirt6 knockout (KO) and wild-type (WT) mice.
• Induction of full-thickness excisional skin lesions.
• Assessment of wound closure, collagen deposition, and angiogenesis.
• Immunohistochemical, flow cytometric, and gene-expression analyses of macrophage subpopulations.
• Analysis of keratinocyte and fibroblast migration in response to conditioned media.
• Investigation of downstream signaling pathways, including Akt signaling.

Main Results:

• Wound closure was significantly delayed in Sirt6 KO mice compared to WT mice.
• Sirt6 deficiency led to increased M1 macrophage infiltration and decreased M2 macrophage numbers in wound tissues.
• KO mice showed reduced collagen deposition, suppressed angiogenesis, and downregulated wound healing-related genes.
• Impaired Akt signaling was identified as a key factor in the reduced M2 phenotypic switching in KO mice.
• Conditioned medium from KO macrophages resulted in slower migration of keratinocytes and fibroblasts.

Conclusions:

• Myeloid cell-specific Sirtuin 6 (Sirt6) deficiency impairs skin wound healing in mice.
• Sirt6 deficiency disrupts macrophage polarization, favoring an M1 phenotype and hindering M2 switching.
• Impaired Akt signaling contributes to the detrimental effects of Sirt6 deficiency on wound repair.
• Targeting Sirt6 in myeloid cells represents a potential therapeutic strategy for enhancing wound healing.