Restoration of the healing microenvironment in diabetic wounds with matrix-binding IL-1 receptor antagonist

Jean L. Tan, Blake Lash, Rezvan Karami, Bhavana Nayer, Yen-Zhen Lu, Celeste Piotto, Ziad Julier, Mikaël M. Martino

Research output: Contribution to journalArticleResearchpeer-review

22 Citations (Scopus)

Abstract

Chronic wounds are a major clinical problem where wound closure is prevented by pathologic factors, including immune dysregulation. To design efficient immunotherapies, an understanding of the key molecular pathways by which immunity impairs wound healing is needed. Interleukin-1 (IL-1) plays a central role in regulating the immune response to tissue injury through IL-1 receptor (IL-1R1). Generating a knockout mouse model, we demonstrate that the IL-1–IL-1R1 axis delays wound closure in diabetic conditions. We used a protein engineering approach to deliver IL-1 receptor antagonist (IL-1Ra) in a localised and sustained manner through binding extracellular matrix components. We demonstrate that matrix-binding IL-1Ra improves wound healing in diabetic mice by re-establishing a pro-healing microenvironment characterised by lower levels of pro-inflammatory cells, cytokines and senescent fibroblasts, and higher levels of anti-inflammatory cytokines and growth factors. Engineered IL-1Ra has translational potential for chronic wounds and other inflammatory conditions where IL-1R1 signalling should be dampened.

Original languageEnglish
Article number422
Number of pages11
JournalCommunications Biology
Volume4
Issue number1
DOIs
Publication statusPublished - Dec 2021

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