RICK/RIP2 Mediates Innate Immune Responses Induced through Nod1 and Nod2 but Not TLRs

Abstract

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 γ-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-γ, 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.

RIP kinases: key decision makers in cell death and innate immunity

“…149,150 However, a more recent report, using synthetic and highly purified forms of TLR ligands, contend that TLR signalling is intact in cells from RIP2 null mice, but loss of RIP2 leads to abrogation of signalling in response to stimulation of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and NOD2 by their specific ligands or the intracellular pathogen Listeria monocytogenes. 151 These findings indicate that RIP2 mediates NOD1 and NOD2 signalling but not TLR signal transduction. NOD1 and NOD2 are cytosolic receptors for bacterial peptidoglycan derivatives such as muramyl dipeptide (MDP) and are expressed highly in mucosal epithelium.…”

Chronic stimulation of Nod2 mediates tolerance to bacterial products

“…This may be due to the initial up-regulation of a number of signaling molecules in the pathway including MyD88 (5,26). In addition, Nod2 interacts with a number of proteins such as procaspase-1, RIP2, and GRIM-19 (27)(28)(29), which could participate in proinflammatory pathways separate from TLR signaling. In contrast, upon longer MDP pretreatment, we observed increasing self-and cross-tolerance.…”

Molecular characterization and expression analysis of nuclear oligomerization domain proteins NOD1 and NOD2 in grass carp Ctenopharyngodon idella

“…By contrast, NOD2 recognizes muramyl dipeptides, also derived from peptidoglycan, but present both in the Gram-positive and -negative bacteria [12]. Upon ligand recognition, both NOD1 and NOD2 recruit RIPK to the receptors via CARD-CARD interactions, which lead to the activation of NF-kB and MAPK pathways [12,13].…”