Modulation of host cell apoptosis during sepsis by alarmins

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Antimicrobial peptides (alpha- and beta-defensins, and cathelicidins) possess the potent antimicrobial activities against invading microorganisms and contribute to the innate host defense. They not only exhibit potent bactericidal activities against Gram-negative and Gram-positive bacteria but also function as immunomodulatory molecules by inducing cytokine and chemokine production, and inflammatory and immune cell activation. Neutrophil is a critical effector cell in host defense against microbial infection, and its lifespan is regulated by various pathogen- and host-derived substances. We previously revealed that human cathelicidin LL-37 and human beta-defensin (hBD)-3 suppress neutrophil apoptosis via the actions on P2X_7 nucleotide receptor and CC chemokine receptor (CCR) 6, respectively. Here, to further evaluate the role of human alpha-defensins in innate immunity, we investigated the action of human neutrophil peptides (HNPs)-1～-3 on neutrophil apoptosis.Neutrophil apoptosis was assessed using human blood neutrophils based on the morphological changes. Of note, HNP-1 most potently suppressed neutrophil apoptosis among HNP-1～-3, accompanied with the downregulation of truncated Bid (a proapoptotic protein), upregulation of Bcl-xL (an antiapoptotic protein), and inhibition of mitochondrial membrane potential change and caspase 3 activity. Interestingly, a selective P2Y_6 antagonist MRS2578 abolished the suppression of neutrophil apoptosis induced by HNP-1 as well as UDP (a P2Y_6 ligand).Collectively, these observations suggest that HNPs, especially HNP-1, can not only kill bacteria but also modulate (suppress) neutrophil apoptosis possibly via the P2Y_6 signaling. Considering their antiapoptotic action, antimicrobial peptides (LL-37, hBD-3 and HNP-1) are expected to exert an advantageous effect on host defense against bacterial infections by prolonging the lifespan of neutrophil, a major phagocyte engaged in the killing of invaded bacteria.