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

Abstract

We recently reported that myeloid cell-expressed sirtuin 6 (Sirt6) plays a crucial role in M1 macrophage polarization and chemotaxis. Given the prominent role of macrophages during wound repair and macrophage heterogeneity, we hypothesized that a Sirt6 deficiency in myeloid cells would delay skin wound closure by affecting the phenotypes of macrophages in wounds. To address this question, a full-thickness excisional lesion was made in the dorsal skin of myeloid cell-specific Sirt6 knockout (KO) and wild-type mice. Wound closure was delayed in the KO mice, which exhibited less collagen deposition, suppressed angiogenesis, and reduced expression of wound healing-related genes compared to the wild-type mice. Using immunohistochemical, flow cytometric, and gene-expression analyses of macrophage subpopulations from wound tissue, we identified increased infiltration of M1 macrophages with a concomitant decrease in M2 macrophage numbers in the KO mice compared to the wild-type mice. Consistent with the in vivo wound closure defects observed in the KO mice, keratinocytes and fibroblasts treated with KO macrophage-derived conditioned medium migrated slower than those treated with wild-type macrophage-derived conditioned medium. An analysis of downstream signaling pathways indicated that impaired Akt signaling underlies the decreased M2 phenotypic switching in KO mice. These results suggest that a macrophage phenotypic switch induced by Sirt6 deficiency contributes to impaired wound healing in mice.

A novel SIRT6 activator ameliorates neuroinflammation and ischemic brain injury via EZH2/FOXC1 axis

“…SIRT6 plays an essential role in the pathogenesis of systemic inflammation 22 but whether SIRT6 regulates neuroinflammation remains unknown. SIRT6 activator could be used as a pharmacological tool to investigate its role in neuroinflammation.…”

“…SIRT6 is highly expressed in the brain and decreased SIRT6 expression was associated with enhanced production of inflammatory factors, such as high mobility group B1 (HMGB1) on ischemic stroke 21 . In addition, SIRT6 deficiency could also delay wound healing in mice by modulating inflammation and macrophage phenotypes 22 . Prognosis of ischemic brain injury alters gene expressions through neuroinflammation-induced chromatin changes 23 .…”

Lipin-1 Contributes to IL-4 Mediated Macrophage Polarization

“…Macrophage polarization is critical for effective in vivo wound healing where the number and phenotype of the resident and recruited macrophages determine the extent and efficiency of healing (36). Up to 1 day after wounding, pro-inflammatory macrophages initiate an acute inflammatory response; after that time frame, wound healing macrophages promote angiogenesis and tissue formation (37).…”

Lipin-1 contributes to IL-4 mediated macrophage polarization

“…Macrophage polarization is critical for effective in vivo wound healing where the number and phenotype of the resident and recruited macrophages determine the extent of healing [30]. Up to 1 day after wounding, pro-inflammatory macrophages initiate an acute inflammatory response and during late phase, wound healing macrophages promote angiogenesis and tissue formation [31].…”