Abstract
NOD1 belongs to the family of NOD-like receptors, which is a group of well-characterised, cytosolic pattern-recognition receptors. The best-studied function of NOD-like receptors is their role in generating immediate pro-inflammatory and antimicrobial responses by detecting specific bacterial peptidoglycans or by responding to cellular stress and danger-associated molecules. The present study describes a regulatory, peptidoglycan-independent function of NOD1 in anti-inflammatory immune responses. We report that, in human dendritic cells, NOD1 balances IL-10-induced STAT1 and STAT3 activation by a SOCS2-dependent mechanism, thereby suppressing the tolerogenic dendritic cell phenotype. Based on these findings, we propose that NOD1 contributes to inflammation not only by promoting pro-inflammatory processes, but also by suppressing anti-inflammatory pathways.
Highlights
NOD-like receptors (NLRs) comprise a family of cytosolic pattern recognition receptors (PRRs) that serves as a first line of defence against invading pathogens
Stimulation of immature dendritic cells (iDCs) with iE-DAP resulted in enhanced tnfα expression, which was significantly decreased by the presence of IL-10 (Supplementary Fig. S1)
We found that IL-10-induced cells, in which NOD1-expression was targeted, expressed significantly higher amounts of il[10] and march[1] (Fig. 1a), whereas reduction of NOD2 had no effect on target gene expression (Fig. 1b)
Summary
NOD-like receptors (NLRs) comprise a family of cytosolic pattern recognition receptors (PRRs) that serves as a first line of defence against invading pathogens. In vivo studies utilising a model of colitis-associated colon tumourigenesis revealed that NOD1-deficient mice are prone to develop inflammation-induced tumours In the latter, transfer of wild-type bone marrow was sufficient to rescue NOD1-deficient mice from developing tumours[11, 12]. Tumouror stroma-derived factors usually promote the differentiation and accumulation of tolerogenic DCs, blocking anti-tumour immunity[24, 25]. Both naturally occurring and induced tolerogenic DCs are characterised by low expression of interleukin (IL)-12 and high IL-10 secretion[26]. In human DCs, decreased NOD1 levels promote a tolerogenic DC phenotype and alter IL-10-induced STAT signalling by a mechanism involving SOCS2
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