DAMPs and PAMPs have distinct roles in neutrophil recruitment during cutaneous microbial infections

Intradermal infections with C. albicans are eliminated by neutrophils recruited at the site of infection with an unknown mechanism. To dissect how neutrophils are recruited at the site of infection, we analyzed the involvement of PRR that recognize C. albicans (TLR4, TLR2, Dectin1 and Dectin2) as well as CARD9, activated downstream Dectins, and MyD88 that transduces the signal derived from TLRs. WT, PRR-deficient and CARD9-deficient mice did not show any defect in neutrophil recruitment after C. albicans intradermal injection. Diversely, MyD88-deficient mice do not recruit neutrophils after C. albicans skin infection. Since MyD88 is involved in IL-1 signaling, we tested the role of IL-1β and IL-1α, two vasoactive cytokines, in the initiation of inflammation and neutrophil recruitment. In vitro and in vivo studies revealed that both IL-1β and IL-1α were involved in this process. IL-1α is constitutively expressed in epithelial, endothelial and stromal cells and can be released through proteolytic cleavage or cell death, enhancing the production of CXCL1, a chemokine with neutrophil chemoattractant activity. We confirmed that CXCL1 production in vivo depends on IL-1α release. We concluded that PRRs were not involved in the initiation of the inflammatory process during primary Candida skin exposure. Diversely, the initiation of the inflammatory process during primary infection can be due to the unspecific release of alarmins (like IL-1α) by distressed cells, considered like DAMP, stimulating neutrophils recruitment at the site of infection. To investigate whether DAMPs and PAMPs could have distinct roles in neutrophil recruitment during microbial infections, we have used models of skin infection with different types of pathogens: a fungus, C. albicans, a Gram-positive bacterium Staphylococcus aureus and a Gram-negative, Pseudomonas aeruginosa.