Nod2 deficiency impairs inflammatory and epithelial aspects of the cutaneous wound healing response.

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Abstract

Infection is a significant causative factor in human chronic wounds which fail to heal. Complex innate host response mechanisms have evolved whereby potentially harmful pathogens are recognised by multiple host pattern recognition receptors (PRRs), yet understanding of PRR function, or dysfunction, in the context of chronic wounds remains limited. NOD2, a cytoplasmic PRR has been strongly implicated in chronic inflammation of the gut, where loss-of-function mutations have been linked to Crohn's disease; however, cutaneous Nod2 function remains poorly characterised. Here we demonstrate an important role for Nod2 in murine skin wound healing. Cutaneous Nod2 is induced in key wound cell types in response to injury. In the absence of Nod2, mice display a substantial delay in acute wound repair associated with epithelial and inflammatory changes. Specifically, Nod2 null mice display altered epidermal migration and proliferation, an initial delay in neutrophil recruitment associated with decreased expression of the chemokine receptor CXCR2, and reduced numbers of alternatively activated macrophages (Ym1(+) cells). Somewhat surprisingly, these Nod2 null phenotypes were associated with little or no expression change in other PRR's, even though compensatory mechanisms have been shown to exist. In this study we show that healing in TLR2 null mice was essentially normal. These findings reveal a novel intrinsic role for Nod2 in cutaneous wound repair in addition to its role in recognising invading pathogens. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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