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FASEB J. 2017 Mar;31(3):868-881. doi: 10.1096/fj.201600856R. Epub 2016 Nov 30.

Interleukin-10-mediated regenerative postnatal tissue repair is dependent on regulation of hyaluronan metabolism via fibroblast-specific STAT3 signaling.

Author information

1
Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
2
Division of Immunology, Department of Pediatrics, Stanford University, Stanford, California, USA.
3
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University, Stanford, California, USA.
4
Center for Children's Surgery, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA.
5
Matrix Biology Program, Benaroya Research Institute, Seattle, Washington, USA; and.
6
Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, California, USA.
7
Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA; keswani@bcm.edu.

Abstract

The cytokine IL-10 has potent antifibrotic effects in models of adult fibrosis, but the mechanisms of action are unclear. Here, we report a novel finding that IL-10 triggers a signal transducer and activator of transcription 3 (STAT3)-dependent signaling pathway that regulates hyaluronan (HA) metabolism and drives adult fibroblasts to synthesize an HA-rich pericellular matrix, which mimics the fetal regenerative wound healing phenotype with reduced fibrosis. By using cre-lox-mediated novel, inducible, fibroblast-, keratinocyte-, and wound-specific STAT3-knockdown postnatal mice-plus syngeneic fibroblast cell-transplant models-we demonstrate that the regenerative effects of IL-10 in postnatal wounds are dependent on HA synthesis and fibroblast-specific STAT3-dependent signaling. The importance of IL-10-induced HA synthesis for regenerative wound healing is demonstrated by inhibition of HA synthesis in a murine wound model by administering 4-methylumbelliferone. Although IL-10 and STAT3 signaling were intact, the antifibrotic repair phenotype that is induced by IL-10 overexpression was abrogated in this model. Our data show a novel role for IL-10 beyond its accepted immune-regulatory mechanism. The opportunity for IL-10 to regulate a fibroblast-specific formation of a regenerative, HA-rich wound extracellular matrix may lead to the development of innovative therapies to attenuate postnatal fibrosis in organ systems or diseases in which dysregulated inflammation and HA intersect.-Balaji, S., Wang, X., King, A., Le, L. D., Bhattacharya, S. S., Moles, C. M., Butte, M. J., de Jesus Perez, V. A., Liechty, K. W., Wight, T. N., Crombleholme, T. M., Bollyky, P. L., Keswani, S. G. Interleukin-10-mediated regenerative postnatal tissue repair is dependent on regulation of hyaluronan metabolism via fibroblast-specific STAT3 signaling.

KEYWORDS:

extracellular matrix; fibrosis; inflammatory cytokines; scarless; wound healing

PMID:
27903619
PMCID:
PMC5295728
DOI:
10.1096/fj.201600856R
[Indexed for MEDLINE]
Free PMC Article

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