Distinct Mechanisms of Type 3 Secretion System Recognition Control LTB4Synthesis in Neutrophils versus Macrophages

Abstract

AbstractLeukotriene B4 (LTB4) is critical for initiating the inflammatory cascade in response to infection. However,Yersinia pestiscolonizes the host by inhibiting the timely synthesis of LTB4and inflammation. Here, we show that the bacterial type 3 secretion system (T3SS) is the primary pathogen associated molecular pattern (PAMP) responsible for LTB4production by leukocytes in response toYersiniaandSalmonella, but synthesis is inhibited by the Yop effectors duringYersiniainteractions. Moreover, we unexpectedly discovered that T3SS-mediated LTB4synthesis by neutrophils and macrophages require two distinct host signaling pathways. We show that the SKAP2/PLC signaling pathway is essential for LTB4production by neutrophils but not macrophages. Instead, phagocytosis and the NLRP3/CASP1 inflammasome are needed for LTB4synthesis by macrophages. Finally, while recognition of the T3SS is required for LTB4production, we also discovered a second unrelated PAMP-mediated signal independently activates the MAP kinase pathway needed for LTB4synthesis. Together, these data demonstrate significant differences in the signaling pathways required by macrophages and neutrophils to quickly respond to bacterial infections.SignificanceThe production of inflammatory lipid mediators by the host is essential for timely inflammation in response to invasion by bacterial pathogens. Therefore, defining how immune cells recognize pathogens and rapidly produce these lipids is essential for us to understand how our immune system effectively controls infection. In this study, we discovered that the host signaling pathways required for leukotriene B4 (LTB4) synthesis differ between neutrophils and macrophages, highlighting important differences in how immune cells respond to infection. Together, these data represent a significant improvement in our understanding of how neutrophils and macrophages rapidly react to bacteria and provide new insights into howYersinia pestismanipulates leukocytes to evade immune recognition to cause disease.