Antimicrobial Peptide Signaling in Skin Diseases

Abstract

Antimicrobial peptides (AMPs) are important innate immune molecules at microbe-host interfaces. The biophysical properties of AMPs that facilitate direct killing of microbes have been extensively reviewed. In this article, we focus on how AMPs perform immunomodulatory functions through interaction with host receptors on epithelial, immune, and neuronal cell types. We summarize the current knowledge of known AMPs in the skin, the receptors that respond to AMPs, and the downstream intracellular signaling pathways. In the end, we discuss the roles of AMP signaling systems in skin diseases.

Keywords: Antimicrobial peptides; Atopic dermatitis; GPCRs; Psoriasis; Rosacea.

Figure 1

Overview of AMP–receptor signaling. AMPs such as cathelicidin (LL-37), defensins (HNP1, hBD2, hBD3), S100 family (S100A7, S100A9, S100A12), and AMP-IBP5 interact with various receptors, including GPCRs (FPR2, MRGPRs, CCRs), P2 receptors (P2X7, P2Y6), TLRs (TLR2, TLR4), GF receptors (EGFR, FGFR), and SRs (SR-B1, RAGE, LRP1), to mediate diverse biological functions. FPR2 is activated by LL-37, causing chemotaxis, superoxide generation, cell survival, and eosinophil lipogenesis. MRGPRX1 is activated by hBD2 and hBD3 and triggers the firing of sensory neurons. MRGPRX2 is activated by LL-37, hBDs, and AMP-IBP5 to mediate mast cell degranulation. Defensins mediate chemotaxis through CCR6 on dendritic cells and T cells and through CCR2 on macrophages. P2X7 is activated by LL-37, hBD3, and HNP1, leading to autophagy, IL-1β production, and pathogen clearance. HNP1 also activates P2Y6, leading to cell survival. LL-37 activates TLR2, whereas S100A9 activates TLR4, resulting in the production of proinflammatory cytokines. LL-37 also interacts with dsDNA, forming an LL-37–DNA complex that is involved in NETosis. The LL-37–DNA complex also activates TLR9, resulting in the secretion of proinflammatory cytokines. EGFR interacts with LL-37, hBD2, and hBD3, leading to cell migration and wound healing. FGFR is activated by hBD3, which leads to fibroblast migration. RAGE is activated by S100A7 and S100A12, leading to leukocyte migration and expression of proinflammatory cytokines. LL-37 also binds with self-coding U1 RNA and is recognized by SR-B1, leading to downstream expression of IFN-β1 and IL-6, and promotes the uptake of oxidized LDL by macrophages. LRP1 interacts with AMP-IBP5, leading to the suppression of AD-like inflammation and promoting keratinocyte migration and proliferation. This figure was made with BioRender. AD, atopic dermatitis; AMP, antimicrobial peptide; dsDNA, double-stranded DNA; FPR, formyl peptide receptor; GPCR, G protein-coupled receptor; hBD, human β-defensin; LDL, low-density lipoprotein; MRGPR, Mas-related G protein-coupled receptor; RAGE, receptor of advanced glycated end products; SR, scavenger receptor; TLR, toll-like receptor.