An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides and restrict intracellular bacterial replication in human macrophages (114.6)

Abstract

Abstract Nod-like receptors (NLRs) emerged as central cytosolic pattern recognition receptors (PRRs). However, the function of the majority of NLRs is currently unknown. We identified that NLRP7 functions as a PRR in primary human macrophages. Activation of NLRP7 by cytosolic microbial acylated lipopeptides (acLP) causes ASC-dependent inflammasome formation in a cytosolic high-molecular weight complex, Caspase-1 activation and maturation and release of interleukin (IL)-1β and IL-18. Reconstitution of an NLRP7/ASC/pro-Caspase-1 inflammasome, but not of an NLRP3/ASC/pro-Caspase-1 inflammasome is sufficient to respond to intracellular delivery of acLP. However, in macrophages both NLRP7 and TLR2 are required for the acLP-mediated release of IL-1β. While TLR2 is necessary for the transcription of pro-IL-1β and pro-IL-18, NLRP7 mediates the Caspase-1-dependent maturation and release of both cytokines. Therefore, NLRP7 and TLR2 contribute to the host defense against intracellular Gram positive bacteria, since knock-down of either NLRP7 or TLR2 promotes intracellular replication of Listeria monocytogenes and knock-down of NLRP7 also increases the intracellular replication of Staphylococcus aures. Our study therefore increases our currently limited understanding of NLR activation, inflammasome assembly and maturation of IL-1β and IL-18 in human macrophages.