RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs.
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 gamma-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-gamma, 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.
Park
Jong-Hwan
JH
University of Michigan Medical School, Department of Pathology and Comprehensive Cancer Center, Ann Arbor, MI 48109, USA.
Kim
Yun-Gi
YG
McDonald
Christine
C
Kanneganti
Thirumala-Devi
TD
Hasegawa
Mizuho
M
Body-Malapel
Mathilde
M
Inohara
Naohiro
N
Núñez
Gabriel
G
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing / Q000819:agonists / Q000172:deficiency / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003960:Diaminopimelic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D007113:Immunity, Innate / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008087:Listeria / Q000276:immunology; D008088:Listeriosis / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D053474:Nod1 Signaling Adaptor Protein / Q000819:agonists / Q000172:deficiency / Q000276:immunology*; D053473:Nod2 Signaling Adaptor Protein / Q000819:agonists / Q000172:deficiency / Q000276:immunology*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000172:deficiency / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic; D008070:Lipopolysaccharides; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D051193:Toll-Like Receptors; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D003960:Diaminopimelic Acid; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2