Mechanoreceptors initiate innate immunity in response to microbial infections

How mammals mount an effective immune response against infectious agents remains an unresolved fundamental issue in biology. Here, we discovered an unforeseen two-tier mechanism of neutrophil recruitment during infections, in which mechanosensing is key to initiating innate immunity. Leveraging a skin infection model and pathogenic bacteria and fungi, we demonstrate that the early recruitment of neutrophils is mainly danger-driven and partly reminiscent of sterile inflammation. Mechanistically, neutrophil recruitment is initiated by a mechanosensor-dependent pathway, involving the activation of PIEZO1 channels. This leads to LTB 4 production, which, along with IL-1⍺, induces the release of CXCL1, promoting neutrophil arrival to the site of infection. In contrast, later neutrophil recruitment is TLR- and CXCL2-dependent, highlighting a shift towards a pathogen-driven response to sustain inflammation. These findings advance our understanding of innate immunity by uncovering that mechanical and biochemical signals integrate into a circuit that initiates innate immune responses to microbial infections.