NLRP12 Modulates Host Defense through IL-17A-CXCL1 Axis

We used an extracellular pathogen Klebsiella pneumoniae to determine the role of NLRP12 since this bacterium is associated with devastating pulmonary infections. We found human myeloid cells (neutrophils and macrophages) and non-myeloid cells (epithelial cells) show upregulation of NLRP12 in human pneumonic lungs. NLRP12 silenced human macrophages and murine Nlrp12(−/−) macrophages displayed reduced activation of NF-κB and MAPK and expression of HDACs following K. pneumoniae infection. NLRP12 is important for the production of IL-1β in human and murine macrophages following K. pneumoniae infection. Furthermore, host survival, bacterial clearance and neutrophil recruitment are dependent on NLRP12 following K. pneumoniae infection. Using bone marrow chimeras, we showed that hematopoietic cell driven NLRP12 signaling predominantly contributes to host defense against K. pneumoniae. Intratracheal administration of either IL-17A+ CD4 T cells or CXCL1+ macrophages rescues host survival, bacterial clearance, and neutrophil recruitment in Nlrp12(−/−) mice following K. pneumoniae infection. These novel findings reveal the critical role of NLRP12-IL-17A-CXCL1 axis in host defense via modulating neutrophil recruitment against this extracellular pathogen.