NLRP6 in Gram-positive Pneumonia and Sepsis

Acute lower respiratory infections (pneumonia) and pneumonia-derived sepsis are among the leading causes of death in the world causing 7.8 million deaths annually. In this regard, Methicillin-resistant Staphylococcus aureus (MRSA) is endemic in the US and implicated for causing high mortality-associated necrotizing pneumonia and aggravating viral pneumonia with superinfection. Additionally, sepsis is the 7th leading cause of death among newborns in the US and is responsible for more than 750,000 hospitalization cases every year. Although there is a plethora of research in both pneumonia and sepsis, the detailed pathophysiology still remains elusive. Understanding the host defense mechanism will help designing better therapeutic interventions to treat such infections. In this context, NLRP6 is a member of Nod-like receptor (NLR) family that has been proposed to regulate microbiota, gut-epithelial integrity, and host defense against Listeria infections. While NLRP6 is expressed in lungs, liver, spleen, and kidneys, its role in sepsis and MRSA-induced pneumonia remains unexplored. Neutrophils play critical role to limit the Staphylococcal infection; however how neutrophils homeostasis is orchestrated during pulmonary MRSA infection remains elusive. Using NLRP6gene-deficient mice, we demonstrate that NLRP6 negatively regulates Gram-positive bacteria-induced pneumonia via regulating phagocytic oxidase activity and cell death mechanism of neutrophils. NLRP6 triggers necroptosis and pyroptosis that reduces phagocytic cells in the lungs. In addition, in a murine model of CLP-induced polymicrobial sepsis, we found that NLRP6 is detrimental for lymphocyte survival and function in the spleen. Furthermore, our data illustrate that MRSA upregulates CXCL5 in order to suppress granulopoiesis and neutrophil trafficking from bone marrow to the lungs. In conclusion, MRSA exploits CXCL5 to suppress the neutrophil accumulation in the lungs as an immune evasion strategy. NLRP6 inflammasome is detrimental during MRSA-induced pneumonia and polymicrobial sepsis. Blocking of NLRP6 could be an effective therapeutic strategy to treat both septic and MRSA-infected patients