ABSTRACT
The innate immune system is critical for clearing infection, and is tightly regulated to avert excessive tissue damage. Nod1/2-Rip2 signaling, which is essential for initiating the innate immune response to bacterial infection and ER stress, is subject to many regulatory mechanisms. In this study, we found that LRRK2, encoded by a gene implicated in Crohn's disease, leprosy and familial Parkinson's disease, modulates the strength of Nod1/2-Rip2 signaling by enhancing Rip2 phosphorylation. LRRK2 deficiency markedly reduces cytokine production in macrophages upon Nod2 activation by muramyl dipeptide (MDP), Nod1 activation by D-gamma-Glu-meso-diaminopimelic acid (iE-DAP) or ER stress. Our biochemical study shows that the presence of LRRK2 is necessary for optimal phosphorylation of Rip2 upon Nod2 activation. Therefore, this study reveals that LRRK2 is a new positive regulator of Rip2 and promotes inflammatory cytokine induction through the Nod1/2-Rip2 pathway.
Subject(s)
Cytokines/immunology , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/immunology , Nod1 Signaling Adaptor Protein/immunology , Nod2 Signaling Adaptor Protein/immunology , Receptor-Interacting Protein Serine-Threonine Kinase 2/immunology , Receptor-Interacting Protein Serine-Threonine Kinases/immunology , Signal Transduction/immunology , Animals , Cytokines/genetics , HEK293 Cells , Humans , Immunity, Innate/genetics , Inflammation/genetics , Inflammation/immunology , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics , Mice , Mice, Knockout , Nod1 Signaling Adaptor Protein/genetics , Nod2 Signaling Adaptor Protein/genetics , Phosphorylation/genetics , Phosphorylation/immunology , Receptor-Interacting Protein Serine-Threonine Kinase 2/genetics , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Signal Transduction/geneticsABSTRACT
Occurrence of new patients of leprosy, caused by Mycobacterium leprae infection, is now almost absent in Japan but is still uncontrolled in developing countries. As one factor affecting the disease development, genetic predisposition of a host has been considered to be associated. Actually, various gene mutations have been reported to be associated at two stages of the disease progression, not only establishment of the disease but also determination of the phenotype, such as lepromatous (L)-type, tuberculoid (T)-type and reversal reaction. On the basis of recent progress of the research on innate immunity, here we analyzed single nucleotide polymorphisms (SNPs) of the genes of major bacterial sensor molecules expressed in antigen-presenting cells, TLR2, DC-SIGN, NOD1 and NOD2, in Japanese leprosy patients. As a result, frequency of polymorphisms in DC-SIGN -336 showed significant difference between the leprosy patients and the healthy controls, reflecting its role in establishment of the disease. Especially, among those with a particular TLR2 -16934 genotype, frequency of the polymorphisms in DC-SIGN -336 showed significant difference between the patients and the controls, suggesting any cooperation of these SNPs.