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Upon chronic microbial exposure and pattern-recognition receptor (PRR) stimulation, myeloid-derived cells undergo a distinct transcriptional program relative to acute PRR stimulation, with proinflammatory pathways being downregulated. However, other host-response pathways might be differentially regulated, and this concept has been relatively unexplored. Understanding mechanisms regulating chronic microbial exposure outcomes is important for conditions of ongoing infection or at mucosal surfaces, such as the intestine. The intracellular PRR nucleotide oligomerization domain 2 (Nod2) confers the highest genetic risk toward developing Crohn's disease (CD). We previously identified mechanisms mediating downregulation of proinflammatory pathways upon chronic Nod2 stimulation; here we sought to define how chronic Nod2 stimulation regulates bacterial killing. We find that, despite downregulating cytokine secretion upon restimulation through PRR and live bacteria, chronic Nod2 stimulation of human monocyte-derived macrophages enhances bacterial killing; this dual regulation is absent in CD Nod2-risk carriers. We show that chronic Nod2-mediated reprogramming of human monocyte-derived macrophages to a state of enhanced bacterial killing requires upregulated reactive oxygen/nitrogen species pathway function through increased p67phox/p47phox/nitric oxide synthase-2 expression; selectively knocking down each of these genes reverses the enhanced bacterial killing. Importantly, we find that, during chronic Nod2 stimulation, NLRP3/NLRP1 inflammasome-mediated caspase-1 activation with subsequent IL-1 secretion is essential for the subsequent bifurcation to downregulated proinflammatory cytokines and upregulated bacterial killing. Therefore, we identify mechanisms mediating the distinct inflammatory and microbicidal outcomes upon chronic stimulation of the CD-associated protein Nod2.

NLRP1 and NLRP3 inflammasomes are essential for distinct outcomes of decreased cytokines but enhanced bacterial killing upon chronic Nod2 stimulation