The Antimicrobial Peptides Human β-Defensins Induce the Secretion of Angiogenin in Human Dermal Fibroblasts

Abstract

The skin produces a plethora of antimicrobial peptides that not only show antimicrobial activities against pathogens but also exhibit various immunomodulatory functions. Human β-defensins (hBDs) are the most well-characterized skin-derived antimicrobial peptides and contribute to diverse biological processes, including cytokine production and the migration, proliferation, and differentiation of host cells. Additionally, hBD-3 was recently reported to promote wound healing and angiogenesis, by inducing the expression of various angiogenic factors and the migration and proliferation of fibroblasts. Angiogenin is one of the most potent angiogenic factors; however, the effects of hBDs on angiogenin production in fibroblasts remain unclear. Here, we investigated the effects of hBDs on the secretion of angiogenin by human dermal fibroblasts. Both in vitro and ex vivo studies demonstrated that hBD-1, hBD-2, hBD-3, and hBD-4 dose-dependently increased angiogenin production by fibroblasts. hBD-mediated angiogenin secretion involved the epidermal growth factor receptor (EGFR), Src family kinase, c-Jun N-terminal kinase (JNK), p38, and nuclear factor-kappa B (NF-κB) pathways, as evidenced by the inhibitory effects of specific inhibitors for these pathways. Indeed, we confirmed that hBDs induced the activation of the EGFR, Src, JNK, p38, and NF-κB pathways. This study identified a novel role of hBDs in angiogenesis, through the production of angiogenin, in addition to their antimicrobial activities and other immunomodulatory properties.

Antimicrobial Peptides and Interleukins in Cleft Soft Palate

“…Furthermore, HBD-2 has different effects on fibroblast activity in connective tissue. A study conducted in 2022 by Umehara et al showed that HBD-2 induces angiogenin secretion via dermal fibroblasts, supporting angiogenesis, which is particularly beneficial in chronic wounds [71]. HBD-2 also induces human conjunctival fibroblast proliferation, gene expression, and the synthesis of fibroblast collagenase (MMP1), which is required for extracellular matrix remodulation and supporting cell migration during wound healing [72].…”

The immune function of dermal fibroblasts in skin defence against pathogens

“…19 HBDs also function in angiogenesis by promoting angiogenin production in dermal fibroblasts. 45 Whether dermal fibroblasts express other antimicrobial peptides upon microbial challenge is less well understood. However, recent work has observed that a subcluster of dermal fibroblasts can proliferate and differentiate into adipocytes, releasing plenty of antimicrobial peptide cathelicidin in response to S. aureus dermal infection.…”

“…An in vitro study has shown that human α‐defensin 5 (HD5) and HBD2 are released by cultured primary dermal fibroblasts after stimulation of DENV 19 . HBDs also function in angiogenesis by promoting angiogenin production in dermal fibroblasts 45 . Whether dermal fibroblasts express other antimicrobial peptides upon microbial challenge is less well understood.…”

Frontiers in Antimicrobial Biomaterials

“…Umehara et al studied the well-characterized skin-derived human β-defensins antimicrobial peptides and demonstrated their influence on the secretion of angiogenin, a potent angiogenic factor. They revealed that various human β-defensins can stimulate the production of angiogenin while maintaining their antimicrobial activities and other immunomodulatory properties [ 13 ]. Zhu et al identified a new antimicrobial peptide gene, the Sparanegtin gene from the mud crab Scylla paramamosain , whose transcripts were particularly abundant in the testis of that species.…”