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Review
. 2023 Aug 14;8(1):300.
doi: 10.1038/s41392-023-01553-x.

Mechanisms and regulation of defensins in host defense

Jie Fu  1   2 , Xin Zong  1   2 , Mingliang Jin  1   2 , Junxia Min  3 , Fudi Wang  4   5 , Yizhen Wang  6   7
Affiliations
Review

Mechanisms and regulation of defensins in host defense

Jie Fu et al. Signal Transduct Target Ther. .

Abstract

As a family of cationic host defense peptides, defensins are mainly synthesized by Paneth cells, neutrophils, and epithelial cells, contributing to host defense. Their biological functions in innate immunity, as well as their structure and activity relationships, along with their mechanisms of action and therapeutic potential, have been of great interest in recent years. To highlight the key research into the role of defensins in human and animal health, we first describe their research history, structural features, evolution, and antimicrobial mechanisms. Next, we cover the role of defensins in immune homeostasis, chemotaxis, mucosal barrier function, gut microbiota regulation, intestinal development and regulation of cell death. Further, we discuss their clinical relevance and therapeutic potential in various diseases, including infectious disease, inflammatory bowel disease, diabetes and obesity, chronic inflammatory lung disease, periodontitis and cancer. Finally, we summarize the current knowledge regarding the nutrient-dependent regulation of defensins, including fatty acids, amino acids, microelements, plant extracts, and probiotics, while considering the clinical application of such regulation. Together, the review summarizes the various biological functions, mechanism of actions and potential clinical significance of defensins, along with the challenges in developing defensins-based therapy, thus providing crucial insights into their biology and potential clinical utility.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Introduction to the history of defensin research. a Timeline of defensin characterization, processing and storage mechanisms and antibacterial mechanisms. b Timeline of regulation mechanism of defensin gene. c Timeline of studies on the role of defensin-mediated host immunity in various disease progression. SNP single-nucleotide polymorphism
Fig. 2
Fig. 2
Structural characteristics of defensins from gene to mRNA to protein. The structure of defensin genes and peptides, including the alignment of the enteric and myeloid α-defensins (a, UniProt: P59665), β-defensin (b, UniProt: P60022), and θ-defensin (c, UniProt: P82271) genes are indicated, along with the number of exons and the coding of signal peptides, pro-segment and mature peptides, as well as the location and the disulfide pairing of cysteines and the helical wheel plots and three-dimensional structure
Fig. 3
Fig. 3
Antimicrobial mechanisms of defensin. a The cell membrane structure of G− and G+ bacteria. b Defensins accumulate on the cell membrane before destroying it. c–e Illustrations of the various modes of defensins-mediated cell killing, including the barrel-stave model, the toroidal pore model and the carpet model. f The structure Lipid II; g Cell wall biosynthesis begins in the cytoplasm where UDP-MurNAc-pentapeptide is formed. This soluble precursor is then linked to the membrane carrier bactoprenolphosphate (C55P) by MraY, yielding Lipid I (reaction I). MurG subsequently adds GlcNAc to form Lipid II (reaction II). After the formation of the interpeptide bridge (as seen in reaction III), the monomeric peptidoglycan unit undergoes translocation across the cytoplasmic membrane for incorporation into the cell wall (reaction III). It is noteworthy that this interpeptide bridge formation is limited to some Gram-positive bacteria, as highlighted by research. Note: To better demonstrate the crosstalk mechanism of defensins in regulating immune homeostasis, the intestine containing PCs and mucosal structures was used as the background of the regulatory network
Fig. 4
Fig. 4
Regulation role of defensins in immune homeostasis. a mBD14 promotes B cell proliferation via TLR2 and improves the M1/M2 macrophage balance and induces regulatory T cells. b Mature α-defensins prevent NLRP3 inflammasome activation and the release of IL-1β. c hBD3 is activated by EGFR-mediated MAP kinase and JAK/STAT signaling pathways after H. pylori infection. d By competitively inhibiting the LPS-induced activation of the NF-κB via TLR4, pBD2 can effectively restrict downstream inflammatory cytokine secretion. e HNP1 released by neutrophils enters macrophages to bind to mRNA, and then inhibits mRNA translation of various inflammatory factors. f, g hBD2, hBD3, and HNPs inhibit the secretion of inflammatory cytokine; h mBD2 promotes the maturation of DCs via TLR4 signal. i Defensins recruit various immune cell to clear out dead cells and pathogens. j hBD2 and hBD3 regulates the repair of barrier function via the CCR6-Rho-ROCK signaling pathway. k In a nutrition-deficient state, the continuously activated α-defensins promote the resistance to invasion by enteric pathogens through an mTOR-Hes1-Atoh1-MMP7-α-defensins axis
Fig. 5
Fig. 5
Regulation role of defensins in gut microbiota and intestinal development. a Intestinal microbiota composition in HD5 and Mmp7 transgenic mice. b–e Defensins gene expression maps, including for the small intestine of mice during 0–28d after birth, the esophagus of chicken during 1–28d, the duodenum of chicken during 1–28d and the spleen of chicken from 1 to 28d
Fig. 6
Fig. 6
Defensins in disease. a Human diseases directly or indirectly associated with defensins. b HNP1-3, HD5, HD6, and hBD1-3 are either increased (red arrow) or decreased (aqua arrow) in cancers from different anatomical locations within the human body
Fig. 7
Fig. 7
Signaling pathways of fatty acids-regulated expression of defensins. SCFAs induce the expression of β-defensins via GPR43-STAT3 and GPR43-mTOR-4E-BP signals; sodium butyrate (NaB) induces the expression of β-defensins via TLR2-p38/ERK- NF-κB, HDAC inhibition and EGFR signals; sodium phenylbutyrate (PBA) induces the expression of β-defensins via TLR2/TLR4-p38/ERK-NF-κB and EGFR signals; Caprylic acid and nonanoic acid induce the expression of β-defensins via HDAC inhibition-acetylation H3K9
Fig. 8
Fig. 8
Signaling pathways of amino acids, vitamin D and plant extracts regulate the expression of defensins. Top left: l-isoleucine induces the expression of β-defensins via the SIRT1/ERK/90RSK signals, and G-protein coupled receptor-ERK pathways. Top right: 25OH vitamin D3 (25D3) induces the expression of β-defensins via TLR2-NF-κB-CYP271B/CYP24-VDR signals. Bottom: Avocado sugar via TLR2-ERK1/2, EGCG, and DA via p38, Reishi via TLR4, and b-Glucan via Dectin-1-Syk-Ikk-NF-κB regulate the expression and section of defensins
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