Microbial adhesion promotes Piezo1 activation to initiate innate immunity

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)B4 production. Together with interleukin (IL)-1α, LTB4 induces CXCL1 release, triggering neutrophil infiltration via the same circuit at play during sterile inflammation. In 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 novel paradigm of how immune responses to infection are initiated.