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Selective recruitment of non-classical monocytes promotes skeletal muscle repair.

ABSTRACT: Regeneration of traumatic defects in skeletal muscle requires the synchronized behavior of multiple cells that participate in repair. The inflammatory cascade that is rapidly initiated after injury serves as a powerful node at which to guide the progression of healing and influence tissue repair. Here, we examine the role that myeloid cells play in the healing of traumatic skeletal muscle injury, and leverage their pro-regenerative functions using local delivery of the immunomodulatory small molecule FTY720. We demonstrate that increasing the frequency of non-classical monocytes in inflamed muscle coincides with increased numbers of CD206+ alternatively activated macrophages. Animals treated with immunomodulatory materials had greater defect closure and more vascularization in the acute phases of injury. In the later stages of repair, during which parenchymal tissue growth occurs, we observed improved regeneration of muscle fibers and decreased fibrotic tissue following localization of pro-regenerative inflammation. These results highlight non-classical monocytes as a novel therapeutic target to improve the regenerative outcome after traumatic skeletal muscle injury.

SUBMITTER: San Emeterio CL

PROVIDER: S-EPMC5218730 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Selective recruitment of non-classical monocytes promotes skeletal muscle repair.

San Emeterio Cheryl L CL Olingy Claire E CE Chu Yihsuan Y Botchwey Edward A EA

Biomaterials 20161116

Regeneration of traumatic defects in skeletal muscle requires the synchronized behavior of multiple cells that participate in repair. The inflammatory cascade that is rapidly initiated after injury serves as a powerful node at which to guide the progression of healing and influence tissue repair. Here, we examine the role that myeloid cells play in the healing of traumatic skeletal muscle injury, and leverage their pro-regenerative functions using local delivery of the immunomodulatory small mol ...[more]

PMID: 27930948

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Project description:BackgroundClosing mucosal defects to reach mucosal healing is an important goal of therapy in inflammatory bowel disease (IBD). Among other cells, monocyte-derived macrophages are centrally involved in such intestinal wound healing. We had previously demonstrated that the anti-α4β7 integrin antibody vedolizumab blocks the recruitment of non-classical monocytes as biased progenitors of wound healing macrophages to the gut and delays wound healing. However, although important for the interpretation of disappointing results in recent phase III trials in IBD, the effects of the anti-β7 antibody etrolizumab on wound healing are unclear so far.MethodsWe analyzed the expression of etrolizumab targets on human and mouse monocyte subsets by flow cytometry and assessed their function in adhesion and homing assays. We explored wound-associated monocyte recruitment dynamics with multi-photon microscopy and compared the effects of etrolizumab and vedolizumab surrogate (-s) antibodies on experimental wound healing and wound-associated macrophage abundance. Finally, we investigated wound healing macrophage signatures in the large intestinal transcriptome of patients with Crohn's disease treated with etrolizumab.ResultsHuman and mouse non-classical monocytes expressed more αEβ7 integrin than classical monocytes and were a target of etrolizumab-s, which blocked non-classical monocyte adhesion to MAdCAM-1 and E-Cadherin as well as gut homing in vivo. Intestinal wound healing was delayed on treatment with etrolizumab-s along with a reduction of peri-lesional wound healing macrophages. Wound healing macrophage signatures in the colon of patients with Crohn's disease were substantially down-regulated on treatment with etrolizumab, but not with placebo.ConclusionsCombined blockade of αEβ7 and α4β7 with etrolizumab seems to exceed the effect of anti-α4β7 treatment on intestinal wound healing, which might help to inform further investigations to understand the recent observations in the etrolizumab phase III trial program.

Dataset Information

Selective recruitment of non-classical monocytes promotes skeletal muscle repair.

Publications

Selective recruitment of non-classical monocytes promotes skeletal muscle repair.

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