Distinct Mechanisms of Type 3 Secretion System Recognition Control LTB₄ Synthesis in Neutrophils versus Macrophages

Leukotriene B4 (LTB₄) is critical for initiating the inflammatory cascade in response to infection. However, Yersinia pestis colonizes the host by inhibiting the timely synthesis of LTB₄ and inflammation. Here, we show that the bacterial type 3 secretion system (T3SS) is the primary pathogen associated molecular pattern (PAMP) responsible for LTB₄ production by leukocytes in response to Yersinia and Salmonella, but synthesis is inhibited by the Yop effectors during Yersinia interactions. Moreover, we unexpectedly discovered that T3SS-mediated LTB₄ synthesis by neutrophils and macrophages require two distinct host signaling pathways. We show that the SKAP2/PLC signaling pathway is essential for LTB₄ production by neutrophils but not macrophages. Instead, phagocytosis and the NLRP3/CASP1 inflammasome are needed for LTB₄ synthesis by macrophages. Finally, while recognition of the T3SS is required for LTB₄ production, we also discovered a second unrelated PAMP-mediated signal independently activates the MAP kinase pathway needed for LTB₄ synthesis. Together, these data demonstrate significant differences in the signaling pathways required by macrophages and neutrophils to quickly respond to bacterial infections.