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Chronic stimulation of Nod2 mediates tolerance to bacterial products.

ABSTRACT: The Toll-like receptor (TLR) and nucleotide-binding oligomerization domain (Nod) families of proteins are critical for bacterial recognition, and, acutely, this frequently leads to proinflammatory responses. Polymorphisms in Nod2 (CARD 15) are associated with an increased likelihood of developing Crohn's disease. However, it is not yet clear how Nod2 dysfunctions lead to defects in human intestinal immune homeostasis. Studies to date have focused on functions after acute, rather than chronic, Nod2 stimulation. However, the intestine is an environment of chronic bacterial product exposure with tolerance to luminal flora. We therefore hypothesized that long-term Nod2 stimulation contributes to down-regulation of inflammatory responses from innate immune receptors. We found that pretreatment with muramyl dipeptide (MDP), a ligand for Nod2, significantly decreased production of the proinflammatory cytokines TNF-alpha, IL-8, and IL-1beta upon Nod2, TLR4, and TLR2 restimulation in primary human monocyte-derived macrophages from a large cohort of individuals. Importantly, TNF-alpha-induced production of proinflammatory cytokines remained intact in these same cells. MDP-stimulated macrophages from Crohn's disease-relevant Leu1007insC Nod2 homozygote individuals were deficient in their ability to cross-tolerize to subsequent treatment with TLR2 and TLR4 ligands. We show that acute Nod2 stimulation induced IRAK-1 activation, and that chronic MDP treatment down-regulated IRAK-1 activation upon Nod2 or TLR4 restimulation. In a subset of individuals, chronic Nod2 stimulation induced expression of the IRAK-1 inhibitory protein IRAK-M. Significantly, intestinal macrophages exhibit tolerance to MDP per production of inflammatory cytokines. These results illustrate a role for chronic stimulation of Nod2 in mediating tolerance to bacterial products.

SUBMITTER: Hedl M

PROVIDER: S-EPMC2148308 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Chronic stimulation of Nod2 mediates tolerance to bacterial products.

Hedl Matija M Li Jing J Cho Judy H JH Abraham Clara C

Proceedings of the National Academy of Sciences of the United States of America 20071121 49

The Toll-like receptor (TLR) and nucleotide-binding oligomerization domain (Nod) families of proteins are critical for bacterial recognition, and, acutely, this frequently leads to proinflammatory responses. Polymorphisms in Nod2 (CARD 15) are associated with an increased likelihood of developing Crohn's disease. However, it is not yet clear how Nod2 dysfunctions lead to defects in human intestinal immune homeostasis. Studies to date have focused on functions after acute, rather than chronic, No ...[more]

PMID: 18032608

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Project description:Background & aimsNucleotide oligomerization domain 2 (Nod2) polymorphisms increase the risk of developing Crohn's disease, which is characterized by chronic intestinal inflammation. Bacterial peptidoglycan products chronically stimulate Nod2 in the intestine. Recent studies found that chronic Nod2 stimulation in human macrophages down-regulates proinflammatory cytokines on Nod2 or Toll-like receptor (TLR) restimulation. Therefore, an emerging hypothesis is that Nod2-mediated cytokine down-regulation is required for intestinal homeostasis, but the mechanisms mediating this down-regulation are incompletely understood.MethodsUtilizing primary human macrophages, we examined secretory mediators as a mechanism of Nod2-mediated tolerance by inhibiting their function and assessing tolerance reversal through cytokine secretion. Signaling pathways contributing to secretory mediator induction and Nod2-mediated tolerance were identified through pathway inhibition.ResultsWe found that chronic Nod2 stimulation cross-tolerizes not only to TLRs but also to the interleukin (IL)-1 receptor. Moreover, chronic IL-1β stimulation down-regulates Nod2 responses. Accordingly, IL-1β blockade partially reverses Nod2-mediated tolerance. We found that an additional essential mechanism for Nod2-mediated tolerance is the early secretion of the anti-inflammatory mediators IL-10, transforming growth factor β, and IL-1Ra. Importantly, the mammalian target of rapamycin (mTOR) pathway, involved in cell growth, differentiation, and activation, significantly contributes to Nod2-induced anti-inflammatory as opposed to proinflammatory cytokines and to Nod2-mediated tolerance.ConclusionsInflammatory responses through the IL-1R are down-regulated upon chronic Nod2 stimulation, secretory mediators are a critical mechanism for Nod2-mediated cytokine down-regulation, and the mTOR pathway is crucial for Nod2-mediated tolerance. These results further contribute to our understanding of the mechanisms through which Nod2, a protein critical to intestinal homeostasis, down-regulates cytokine responses.

Project description:Microbial-induced cytokine regulation is critical to intestinal immune homeostasis. Acute stimulation of nucleotide-binding oligomerization domain 2 (NOD2), the Crohn's disease-associated sensor of bacterial peptidoglycan, induces cytokines. However, cytokines are attenuated after chronic NOD2 and pattern recognition receptor stimulation of macrophages; similar attenuation is observed in intestinal macrophages. The role of Tyro3, Axl, and Mer (TAM) receptors in regulating chronic pattern recognition receptor stimulation and NOD2-induced outcomes has not been examined. Moreover, TAM receptors have been relatively less investigated in human macrophages. Whereas TAM receptors did not downregulate acute NOD2-induced cytokines in primary human macrophages, they were essential for downregulating signaling and proinflammatory cytokine secretion after chronic NOD2 and TLR4 stimulation. Axl and Mer were similarly required in mice for cytokine downregulation after chronic NOD2 stimulation in vivo and in intestinal tissues. Consistently, TAM expression was increased in human intestinal myeloid-derived cells. Chronic NOD2 stimulation led to IL-10- and TGF-β-dependent TAM upregulation in human macrophages, which, in turn, upregulated suppressor of cytokine signaling 3 expression. Restoring suppressor of cytokine signaling 3 expression under TAM knockdown conditions restored chronic NOD2-mediated proinflammatory cytokine downregulation. In contrast to the upregulated proinflammatory cytokines, attenuated IL-10 secretion was maintained in TAM-deficient macrophages upon chronic NOD2 stimulation. The level of MAPK activation in TAM-deficient macrophages after chronic NOD2 stimulation was insufficient to upregulate IL-10 secretion; however, full restoration of MAPK activation under these conditions restored c-Fos, c-Jun, musculoaponeurotic fibrosarcoma oncogene homolog K, and PU.1 binding to the IL-10 promoter and IL-10 secretion. Therefore, TAM receptors are critical for downregulating proinflammatory cytokines under the chronic NOD2 stimulation conditions observed in the intestinal environment.

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Chronic stimulation of Nod2 mediates tolerance to bacterial products.

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Chronic stimulation of Nod2 mediates tolerance to bacterial products.

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