Microbial adhesion promotes Piezo1 activation to initiate innate immunity

Abstract How mammals mount an effective immune response against infectious agents remains unresolved. Here we identify microbial adhesion to myeloid cells as a critical initiating event that precedes pattern recognition receptor (PRR) engagement. Using a skin infection model with pathogenic bacteria and fungi, we demonstrate that neutrophil recruitment occurs in two sequential phases. The early phase is PRR-independent and instead driven by microbial adhesion, which engages the mechanosensitive ion channel Piezo1 to promote leukotriene (LT)B 4 production. Together with interleukin-1α, LTB 4 induces CXCL1 release, triggering neutrophil infiltration via the same circuit at play during sterile inflammation. By contrast, the late phase is toll-like receptor (TLR)- and CXCL2-dependent, marking a transition to the canonical, pathogen-driven response. Our findings uncover microbial adhesion as a previously unrecognized danger signal that activates innate immunity via mechanotransduction, revealing a paradigm of how immune responses to infection are initiated.