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Low-grade inflammatory polarization of monocytes impairs wound healing.

ABSTRACT: Impaired wound healing often accompanies low-grade inflammatory conditions, during which circulating levels of subclinical super-low-dose endotoxin may persist. Low-grade inflammatory monocyte polarization may occur during chronic inflammation and deter effective wound repair. However, little is understood about the potential mechanisms of monocyte polarization by sustained insult of subclinical super-low-dose endotoxin. We observed that super-low-dose endotoxin preferentially programmes a low-grade inflammatory monocyte state in vitro and in vivo, as represented by the elevated population of CD11b(+) Ly6C(high) monocytes and sustained expression of CCR5. Mechanistically, super-low-dose endotoxin caused cellular stress, altered lysosome function and increased the transcription factor IRF5. TUDCA, a potent inhibitor of cellular stress, effectively blocked monocyte polarization and improved wound healing in mice injected with super-low-dose endotoxin. Our data revealed the polarization of low-grade inflammatory monocytes by sustained endotoxin challenge, its underlying mechanisms and a potential intervention strategy. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

SUBMITTER: Yuan R

PROVIDER: S-EPMC4760849 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Low-grade inflammatory polarization of monocytes impairs wound healing.

Yuan Ruoxi R Geng Shuo S Chen Keqiang K Diao Na N Chu Hong Wei HW Li Liwu L

The Journal of pathology 20160125 4

Impaired wound healing often accompanies low-grade inflammatory conditions, during which circulating levels of subclinical super-low-dose endotoxin may persist. Low-grade inflammatory monocyte polarization may occur during chronic inflammation and deter effective wound repair. However, little is understood about the potential mechanisms of monocyte polarization by sustained insult of subclinical super-low-dose endotoxin. We observed that super-low-dose endotoxin preferentially programmes a low-g ...[more]

PMID: 26690561

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Project description:BackgroundThe accumulation of M1-polarized macrophages and excessive inflammation are important in the pathogenesis of diabetic foot ulcer (DFU). However, the underlying mechanism of DFU pathogenesis and the crucial regulators of DFU are less well known. Our previous study reported that kallikrein-binding protein (KBP), an angiogenesis inhibitor, was significantly upregulated in diabetic patients compared to its levels in controls. The effects of KBP on monocyte chemotaxis and macrophage M1 polarization were elucidated in this study.MethodsPlasma KBP levels and monocyte counts were assessed by ELISA and flow cytometry. Wound closure rates in different groups were monitored daily. The phenotype and recruitment of macrophages were measured by real-time PCR, western blot and immunofluorescence assays. The expression of Notch and NF-κB signalling pathway members was determined by the methods mentioned above. ChIP and dual-luciferase reporter gene assays were employed to explore the binding and transcriptional regulation of Hes1 and iNOS.ResultsWe found that plasma KBP levels and circulating monocytes were elevated in diabetic patients compared to those in nondiabetic controls, and both were higher in diabetic patients with DFU than in diabetic patients without DFU. KBP delayed wound healing in normal mice; correspondingly, KBP-neutralizing antibody ameliorated delayed wound healing in diabetic mice. Circulating monocytes and macrophage infiltration in the wound were upregulated in KBP-TG mice compared to those in control mice. KBP promoted the recruitment and M1 polarization of macrophages. Mechanistically, KBP upregulated iNOS by activating the Notch1/RBP-Jκ/Hes1 signalling pathway. Hes1 downregulated CYLD, a negative regulator of NF-κB signalling, and then activated the IKK/IκBα/NF-κB signalling pathway.ConclusionsOur findings demonstrate that KBP is the key regulator of excessive inflammation in DFUs and provide a novel target for DFU therapy.

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Low-grade inflammatory polarization of monocytes impairs wound healing.

Publications

Low-grade inflammatory polarization of monocytes impairs wound healing.

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