RICK Promotes Inflammation and Lethality after Gram-Negative Bacterial Infection in Mice Stimulated with Lipopolysaccharide

Abstract

RICK (receptor-interacting protein-like interacting caspase-like apoptosis regulatory protein kinase), a serine-threonine kinase, functions downstream of the pattern recognition receptors Nod1 and Nod2 to mediate NF-B and mitogen-activated protein kinase (MAPK) activation in response to specific microbial stimuli. However, the function of RICK in the recognition and host defense of gram-negative bacteria remains poorly understood. We report here that infection of wild-type and RICK-deficient macrophages with Pseudomonas aeruginosa and Escherichia coli elicited comparable activation of NF-B and MAPKs as well as secretion of proinflammatory cytokines. However, production of interleukin 6 (IL-6) and IL-1␤ induced by these gramnegative bacteria was impaired in RICK-deficient macrophages when the cells had previously been stimulated with lipopolysaccharide (LPS) or E. coli. The diminished proinflammatory response of RICK-deficient macrophages to bacteria was associated with reduced activation of NF-B and MAPKs. Importantly, mutant mice deficient in RICK were less susceptible than wild-type mice to P. aeruginosa infection when the animals had previously been stimulated with LPS. The reduced lethality of RICK-deficient mice infected with P. aeruginosa was independent of pathogen clearance but was associated with diminished production of proinflammatory molecules in vivo. These results demonstrate that RICK contributes to the induction of proinflammatory responses and susceptibility to gram-negative bacteria after exposure to LPS, a condition that is associated with reduced Toll-like receptor signaling.

The role of nucleotide-binding oligomerization domain 1 during cytokine production by macrophages in response to Mycobacterium tuberculosis infection

“…Pre-exposure with LPS results in macrophages that become tolerant to TLRs, and enhanced Nod1 and Nod2 activities (Kim et al, 2008a,b). Our findings from the current study show that LPS pretreatment adversely affects production levels of IL-6 and IL-1␤ in Nod1-deficient macrophages to a greater extent than in WT cells, which is consistent with other studies showing involvement of Nod1/Nod2 or their adaptor protein Rip2/RICK in cytokines production by LPS-pretreated macrophages in response to live bacteria such as L. monocytogenes, P. aeruginosa, and Y. enterocolitica (Jeong et al, 2013;Kim et al, 2008a,b;Park et al, 2009). These results suggest a synergy between Nod1 and TLRs that induce the host immune response following infection with M. tuberculosis.…”

Up-regulation of Nucleotide-binding Oligomerization Domain 1 in Inflamed Human Dental Pulp

“…RICK acts downstream of NOD-1 to mediate MAPK signaling in response to microbial stimuli (31). In this study, inhibition of p38 MAPK suppressed both IL-8 and MCP-1 secretion stimulated by NOD-1; on the other hand, inhibition of JNK signaling had little effects on NOD-1-induced MCP-1 production.…”

Receptor Interacting Protein 2 (RIP2) Is Dispensable for OVA-Induced Airway Inflammation in Mice

“…Listeria -induced production of cytokines was impaired in NOD1/2 double- or RIP2-deficient macrophages after LPS exposure 37. RIP2 deficiency also led to decreased production of cytokines in TLR-tolerized macrophages in response to Pseudomonas infection, and protected mice from lethality induced by the bacterial infection 38. Therefore, it is necessary to clarify whether NOD1/2 and RIP2 contribute to the control of the development of allergic diseases mediated by microbial infection.…”