Distinct Mechanisms of Type 3 Secretion System Recognition Control LTB Synthesis in Neutrophils versus Macrophages.

Leukotriene B4 (LTB) is critical for initiating the inflammatory cascade in response to infection. However, colonizes the host by inhibiting the timely synthesis of LTB and inflammation. Here, we show that the bacterial type 3 secretion system (T3SS) is the primary pathogen associated molecular pattern (PAMP) responsible for LTB production by leukocytes in response to and , but synthesis is inhibited by the Yop effectors during interactions. Moreover, we unexpectedly discovered that T3SS-mediated LTB synthesis by neutrophils and macrophages require two distinct host signaling pathways. We show that the SKAP2/PLC signaling pathway is essential for LTB production by neutrophils but not macrophages. Instead, phagocytosis and the NLRP3/CASP1 inflammasome are needed for LTB synthesis by macrophages. Finally, while recognition of the T3SS is required for LTB production, we also discovered a second unrelated PAMP-mediated signal independently activates the MAP kinase pathway needed for LTB synthesis. Together, these data demonstrate significant differences in the signaling pathways required by macrophages and neutrophils to quickly respond to bacterial infections.