Activation of NOD2 induces an IL-32 regulated dendritic cell program in leprosy (111.22)

Abstract

Abstract The ability of the innate immune system to recognize and respond to microbial pathogens is determined by the interaction of microbial ligands with host receptors located in specific cellular compartments. For Mycobacterium leprae, tricaylated lipoproteins are recognized by cell surface TLR2/1 and muramyl dipeptide (MDP) by intracellular NOD2. The association of NOD2 polymorphisms with susceptibility to leprosy led us to hypothesize that activation of NOD2 regulates key innate immune host defense pathways in leprosy. We first examined gene expression profiles of monocytes stimulated with NOD2 ligand (MDP) or TLR2/1 ligand (19kD) and compared them to those found in lesions of tuberculoid (T-lep) vs. lepromatous (L-lep) leprosy. NOD2 activation and T-lep lesions are both characterized by DC gene programs. NOD2 activation induces differentiation into CD1b+ DC that are potent antigen presenting cells compared to TLR2/1L-triggered DC. Gene expression analysis and gene knockdown experiments revealed that NOD2-induced DC differentiation is regulated by IL-32. Furthermore, NOD2L activation of monocytes from L-lep patients show reduced induction of IL-32 and CD1b+ DC; however, CD1b expression is rescued by the addition of exogenous IL-32. In conclusion, we provide evidence that NOD2L induces a IL-32-regulated DC program in monocytes, with relevance to the pathogenesis and therapeutic intervention in infectious diseases such as leprosy.