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Cross-Tolerization between Nod1 and Nod2 Signaling Results in Reduced Refractoriness to Bacterial Infection in Nod2-Deficient Macrophages¹

Yun-Gi Kim^*, Jong-Hwan Park^*, Stephanie Daignault, Koichi Fukase and Gabriel Núñez^2,*

^* Department of Pathology and Comprehensive Cancer Center, and Comprehensive Cancer Center Biostatistics Core, The University of Michigan Medical School, Ann Arbor, MI 48109; and Department of Chemistry, Graduate School of Science, Osaka University, Machikaneyama 1–1, Toyonaka, Osaka, Japan

Nod2 is an intracellular innate immune receptor that plays a role in host defense and susceptibility to inflammatory disease. We show in this study that macrophages rendered refractory to TLR4 and Nod2 signaling by exposure to LPS and muramyl dipeptide (MDP) exhibit impaired TNF- and IL-6 production in response to pathogenic Listeria monocytogenes and Yersinia pseudotuberculosis as well as commensal bacteria including Escherichia coli and Bacteroides fragilis. Surprisingly, Nod2 deficiency was associated with impaired tolerization in response to pathogenic and commensal bacteria. Mechanistically, reduced tolerization of Nod2-null macrophages was mediated by recognition of bacteria through Nod1 because it was abolished in macrophages deficient in Nod1 and Nod2. Consistently, Nod2-null macrophages tolerant to LPS and MDP showed enhanced production of TNF- and IL-6 as well as increased NF-B and MAPK activation in response to the dipeptide KF1B, the Nod1 agonist. Furthermore, reduced tolerization of Nod2-deficient macrophages in response to bacteria was abolished when mutant macrophages were also rendered tolerant to the Nod1 ligand. Finally, MDP stimulation induced refractoriness not only to MDP, but also to iE-DAP stimulation, providing a mechanism to explain the reduced tolerization of Nod2-deficient macrophages infected with bacteria. These results demonstrate that cross-tolerization between Nod1 and Nod2 leads to increase recognition of both pathogenic and commensal bacteria in Nod2-deficient macrophages pre-exposed to microbial ligands.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants AI063331 and AI064748 (to G.N.).

² Address correspondence and reprint requests to Dr. Gabriel Núñez, The University of Michigan Medical School, Department of Pathology and Comprehensive Cancer Center, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109. E-mail address: bclx{at}umich.edu

³ Abbreviations used in this paper: NOD, nucleotide-binding oligomerization domain; NLR, NOD-like receptor; MDP, muramyl dipeptide.

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