Hexapeptide induces M2 macrophage polarization via the JAK1/STAT6 pathway to promote angiogenesis in bone repair

Xinyun Han,Junxian Hu,Wenbo Zhao,Hongwei Lu,Jingjin Dai,Qingyi He

doi:10.1016/j.yexcr.2022.113064

Xinyun Han, Junxian Hu + Show 4 more

Open Access

https://doi.org/10.1016/j.yexcr.2022.113064

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Journal: Experimental Cell Research	Publication Date: Feb 12, 2022
Citations: 14	License type: cc-by

Affiliation: Army Medical University

Abstract

Angiogenesis is essential for successful bone defect repair. In normal tissue repair, the physiological inflammatory response is the main regulator of angiogenesis through the activity of macrophages and the cytokines secreted by them. In particular, M2 macrophages which secrete high levels of PDGF-BB are typically considered to promote angiogenesis. A hexapeptide [WKYMVm, (Trp-Lys-Tyr-Met-Val-D-Met-NH2)] has been reported to modulate inflammatory activities. However, the underlying mechanisms by which WKYMVm regulates macrophages remain unclear.In this study, the possible involvement by which WKYMVm induces the polarization of macrophages and affects their behaviors was evaluated. In vitro results showed that macrophages were induced to an M2 rather than M1 phenotype and the M2 phenotype was enhanced by WKYMVm through activation of the JAK1/STAT6 signaling pathway. It was also found that WKYMVm played an important role in the PDGF-BB production increase and proangiogenic abilities in M2 macrophages. Consistent with the results in vitro, the elevated M2/M0 ratio induced by WKYMVm enhanced the formation of new blood vessels in a femoral defect mouse model. These findings suggest that WKYMVm could be a promising alternative strategy for angiogenesis in bone repair by inducing M2 macrophage polarization.

Highlights

Bone defects caused by trauma, infection, cancer, congenital diseases and other factors are common diseases endangering human health [1,2,3]
To determine the effect of WKYMVm-induced M2 macrophages on angiogenesis, we examined the expression of the platelet-derived growth factor-BB (PDGF-BB) gene in bone marrow macrophages (BMMs) and RAW264.7 cells induced by WKYMVm, and the results showed that PDGF-BB expression was upregulated in both cell lines (Fig. 4A)
We focused on JAK1/STAT6 signaling downstream of the WKYMVm receptor FPR2, which is necessary for M2 polarization

Summary

Introduction

Bone defects caused by trauma, infection, cancer, congenital diseases and other factors are common diseases endangering human health [1,2,3]. Macrophages are the key regulators of inflammation-related immunity and have multiple functions (e.g., angiogenesis and injury repair) [6, 7]. Classic macrophages (M1) are activated by microbial agents (lipopolysaccharides and interferon-γ) that have proinflammatory effects. M1 macrophages secrete major inflammatory cytokines, including interleukin (IL)-1β and tumor necrosis factor (TNF)-α, and upregulate enzyme-inducible nitric oxide synthase (iNOS) [10, 11]. The other type of macrophages (M2) are alternately activated by IL-4 or IL-13 and having antiinflammatory effects. M2 macrophages upregulate the enzymes arginase (Arg)-1 and chitinase-like protein 3 (Chil3/Ym1) and produce cytokines, including IL-10 and transforming growth factor (TGF)-β [12,13,14]. It is worth noting that M2 macrophages can promote angiogenesis by secreting high levels of platelet-derived growth factor-BB (PDGF-BB) [15]

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Conclusion