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University of Michigan Medical School, Department of Pathology and Comprehensive Cancer Center, Ann Arbor, MI 48109
RICK is a kinase that has been implicated in Nod1 and Nod2 signaling. In addition, RICK has been proposed to mediate TLR signaling in that its absence confers reduced responses to certain bacterial products such as LPS. We show here that macrophages and mice lacking RICK are defective in their responses to Nod1 and Nod2 agonists but exhibit unimpaired responses to synthetic and highly purified TLR agonists. Furthermore, production of chemokines induced by the bacterial dipeptide 
-D-glutamyl-meso-diaminopimelic acid was intact in MyD88 deficient mice but abolished in RICK-null mice. Stimulation of macrophages with muramyl dipeptide, the Nod2 activator, enhanced immune responses induced by LPS, IFN-, and heat-killed Listeria in wild-type but not in RICK- or Nod2-deficient macrophages. Finally, we show that the absence of RICK or double deficiency of Nod1 and Nod2 was associated with reduced cytokine production in Listeria-infected macrophages. These results demonstrate that RICK functions in innate immunity by mediating Nod1 and Nod2 signaling but not TLR-mediated immune responses.
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 National Institutes of Health Grants AI063331 and AI064748 (to G.N.) and GM-60421 (to N.I.). M.B.-M. was supported by a postdoctoral fellowship from University of Michigan Center for Genetics in Health and Medicine. C.M. was supported by a Career Development Award from the Crohn’s and Colitis Foundation of America.
2 Address correspondence and reprint requests to Dr. Gabriel Núñez University of Michigan Medical School Department of Pathology and Comprehensive Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109. E-mail address: bclx{at}umich.edu
3 Abbreviations used in this paper: NOD, nucleotide-binding oligomerization domain; NLR, nucleotide-binding oligomerization domain-like receptor; BMDM, bone marrow derived macrophage; CARD, caspase-recruitment domain; HKLM, heat-killed Listeria monocytogenes; iE-DAP, -D-glutamyl-meso-diaminopimelic acid; IKK, I
B kinase; KC, keratinocyte-derived chemokine; KO, knockout; LTA, lipoteichoic acid; MDP, muramyl dipeptide; PGN, peptidoglycan; poly(I:C), polyinosinic-polycitidylic acid; WT, wild type.
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