The study shows that the peptide LL‑37 can trigger a specific cell‑surface receptor (FPRL1) in human fibroblast cells, leading to a chain reaction that activates an enzyme complex (NADPH oxidase) and produces superoxide, a type of reactive oxygen species. This effect can be blocked by drugs that inhibit the receptor or downstream signals, confirming the pathway. For DIY health enthusiasts, it suggests that LL‑37 isn’t just antimicrobial—it can also raise oxidative stress in skin cells, which may have implications for aging and tissue health.

Molecular mechanisms underlying the generation of reactive oxygen species in LL-37-stimulated cells are poorly understood. Previously, we demonstrated that in human fibroblasts the exposure to WKYMVm induced p47(phox) phosphorylation and translocation and, in turn, NADPH oxidase activation. These effects were mediated by the activation of the Formyl-peptide receptor-like 1 (FPRL1) and the downstream signaling involved ERKs phosphorylation and PKCalpha- and PKCdelta-activation. Since LL-37 uses FPRL1 as a receptor to mediate its action on several cell types, we investigated in LL-37-stimulated IMR90 cells molecular mechanisms involved in NADPH-dependent superoxide generation. The exposure to LL-37, which is expressed in fibroblasts, induced ERKs activation, p47(phox) phosphorylation and translocation as well as NADPH oxidase activation. These effects were prevented by pertussis toxin, PD098059 and WRWWWW, a FPRL1-selective antagonist. Furthermore, the stimulation with LL-37 of HEK293 cells, transfected to stably express FPRL1, induced a rapid activation of ERKs and p47(phox) phosphorylation.