Significance of host antimicrobial peptides in the pathogenesis and treatment of acne vulgaris

Abstract

Acne vulgaris (AV) is a chronic inflammatory condition of the pilosebaceous units characterized by multiple immunologic, metabolic, hormonal, genetic, psycho-emotional dysfunctions, and skin microbiota dysbiosis. The latter is manifested by a decreased population (phylotypes, i.e., genetically distinct bacterial subgroups that play different roles in skin health and disease) diversity of the predominant skin bacterial commensal - Cutinbacterium acnes. Like in other dysbiotic disorders, an elevated expression of endogenous antimicrobial peptides (AMPs) is a hallmark of AV. AMPs, such as human β-defensins, cathelicidin LL-37, dermcidin, or RNase-7, due to their antibacterial and immunomodulatory properties, function as the first line of defense and coordinate the host-microbiota interactions. Therefore, AMPs are potential candidates for pharmaceutical prophylaxis or treating this condition. This study outlines the current knowledge regarding the importance of AMPs in AV pathomechanism in light of recent transcriptomic studies. In particular, their role in improving the tight junctions (TJs) skin barrier by activating the fundamental cellular proteins, such as PI3K, GSK-3, aPKC, and Rac1, is discussed. We hypothesized that the increased expression of AMPs and their patterns in AV act as a compensatory mechanism to protect the skin with an impaired permeability barrier. Therefore, AMPs could be key determinants in regulating AV development and progression, linking acne-associated immune responses and metabolic factors, like insulin/IGF-1 and PI3K/Akt/mTOR/FoxO1 signaling pathways or glucotoxicity. Research and development of anti-acne AMPs are also addressed.

Keywords: Cutibacterium acnes; acne vulgaris; antimicrobial peptides; inflammation; skin dysbiosis.

Figure 1

Composition of the skin microbiota. The graph was created based on data collected by the Skin Microbial Genome Collection (SMGC) project. The figure’s information summarizes the published experimental work results (6).

Figure 2

Antimicrobial peptides (AMPs) genes upregulation fold change (AV involved vs. non-involved skin) estimated by the microarray transcriptomic analysis of biopsies from early inflammatory AV lesions, i.e., comedones shading into small red papules, collected from twenty subjects with moderate to severe AV reported by Kelhälä et al. (21); 3D protein models were obtained from RCSB Protein Data Bank (https://www.rcsb.org).

Figure 3

Role of AMPs in AV pathomechanism.

Figure 4

Relationship between AMPs and the modulation of epidermal TJs barrier function in AV metabolic background context. Details are discussed in the text with the use of citations. All information presented in the figure summarizes the results of the published experimental work (, –112).

Figure 5

Role of C. acnes in skin health and AV pathomechanism.

Figure 6

The pathomechanism of AV. Abbreviations: CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; HPA axis, hypothalamic-pituitary-adrenal axis; HPG axis, hypothalamic-pituitary-gonadal axis; GnRH, gonadotropin-releasing hormone; MC4R, melanocortin receptor 4.

Figure 7

Functional association networks between AMPs and AV metabolic background obtained from String database with cluster analysis (k-means clustering, dotted lines represent edges between clusters) (last accessed 17.03.2024) (177). DEFB1, human β-defensin 1 (hBD-1); DEFB4A, human β-defensin 2 (hBD-2); DEFB103, human β-defensin 3 (hBD-3); S100A7, psoriasin; S100A8, calgranulin A; S100A9, calgranulin B; S100A12, calgranulin C; S100A7A, S100A15 (koebnerisin); SLPI, secretory leukocyte protease inhibitor; PI3, elafin; LTF, lactoferrin; DCD, dermcidin; LYZ, lysozyme; RNASE7, Ribonuclease 7; CAMP, cathelicidin LL-37; LCN2, lipocalin 2 (neutrophil gelatinase-associated lipocalin); GNLY, granulysin; GZMB, granzyme B; ELANE, neutrophil elastase; TAC1, substance B; PI3KCA, phosphoinositide 3-kinase; PRKC1, atypical protein kinase C (aPKC); RAC1, Ras-related C3 botulinum toxin substrate 1; INS, insulin; IGF1 - insulin-like growth factor 1; IFGF1R, insulin-like growth factor 1 receptor; AKT1, RAC-alpha serine/threonine-protein kinase; MTOR, Serine/threonine-protein kinase mTOR; FOXO1, forkhead box protein O1.

Figure 8

The physicochemical parameters of the developed anti-acne AMPs (n=42) discussed in the text; the graphs were created based on the AMPs parameters calculated using the ProtParam tool, using the website (https://web.expasy.org/protparam/), additional information included in Supplementary Table S1 . The information in the figure summarizes the results of published experimental work (, –257).