The potential role of H₂S in the anti-infective function of antimicrobial peptides

Antimicrobial peptides (AMPs) are essential components of the innate immune system in animals, playing crucial roles in defending against microbial infections. Hydrogen sulfide (H₂S), a vital gasotransmitter, is involved in regulating a wide array of physiological functions. However, the role of H₂S in the anti-infective actions of AMPs remains poorly understood. Here, we demonstrate the crucial role of H₂S in mediating the anti-infective functions of AMPs across diverse animal species. LL-37/CRAMP, the human cathelicidin family AMP and its mouse homolog, induce H₂S production predominantly through 3-mercaptopyruvate sulfurtransferase (3MST) in Escherichia coli and Clostridium perfringens. The generated H₂S further participates in reactive oxygen species (ROS) accumulation, leading to bacterial death by oxidative damage. Additionally, LL-37 activates the Akt signaling pathway, upregulating cystathionine γ-lyase (CSE) expression to generate H₂S in macrophages. This process plays a potential role in facilitating the immunomodulatory activity of LL-37/CRAMP and we confirmed that H₂S is involved in their in vivo anti-infective activity of LL-37. Moreover, besides LL-37/CRAMP, we reveal that AMPs from various animal species also induce H₂S production in bacteria and macrophages. Overall, our findings highlight a previously unrecognized role of H₂S in AMP anti-infective function, which is ubiquitous across AMPs from different animals.