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. During inflammation, the recruitment of circulating neutrophils into tissue is one of the early events and it has been linked with the rapid containment of infections. This process, traditionally associated with the expression of pattern recognition receptors (PRRs) and with pathogen recognition, appears to be more strongly influenced by tissue damage signals. Among them, tissue detection of mechanical stress has been recently linked to the activation of immune cells during inflammation. Building on these observations, we sought to identify the signals that trigger the beginning of the inflammatory process during microbial infections. To do so, we utilized a skin infection model wherein microbes (Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa) are injected intradermally to minimize tissue damage while introducing PAMPs in substantial amounts. To study the molecular mechanism leading to neutrophil recruitment, we characterized the immune infiltration through multi-parametric flow cytometry and multiplexed imaging and the molecular cascade through qPCR and ELISA, both in WT and mice KO for PRRs or interleukin receptors. Moreover, results in KO mice were validated with pharmacological and genetic approaches. Here, we discovered an unforeseen two-tier mechanism of neutrophil recruitment during infections, in which mechanoenzyme is key to initiating innate immunity. Mechanistically, neutrophil recruitment is initiated by a mechanosensory-dependent pathway, involving the activation of PIEZO1 channels. This leads to LTB4 production, which, along with IL-1a, induces the release of CXCL1, promoting neutrophil arrival to the site of infection. In contrast, at alter time points neutrophil recruitment is TLR- and CXCL2-dependent, highlighting a shift towards a pathogen-driven response to sustain inflammation.