Defensin-1

Human β-defensin 1 (hBD-1) is a multifaceted antimicrobial peptide being a tumour suppressor and, depending on call of duty, capable of inducing self-nets and neutrophil extracellular traps (NETs) to capture and/or kill bacteria, participates in inflammatory responses in chronic diseases including hBD-3 upregulation and also capable of up/downregulation in the presence of certain species of Lactobacillus sp. Thus, is regulated by host microbiota. Alleles, genotypes and/or altered gene expression of its coding gene, DEFB1, have been associated with several human diseases/conditions ranging from metabolic/chronic (e.g. cancer), infectious (e.g. tuberculosis, HIV/AIDS), inflammatory (gastrointestinal diseases), male infertility and more recently, neurologic (e.g. depression and Alzheimer) and autoimmune diseases (e.g. vitiligo and systemic lupus erythematosus). The present update focuses on novel DEFB1/hBD-1 properties and biomarker features, its biological function and the pharmaceutical potential uses of antimicrobial peptide elicitors (APEs) or the engineered peptide in the treatment of hBD-1-related human diseases.

Objectives: The purpose of this meta-analysis was to reveal a potential association of the four functional polymorphisms in human Beta-defensin 1 (DEFB1) gene: rs1047031(c*5G > A) at 3'UTR and rs11362 (-20 G > A), rs1800972(-44 C > G), and rs1799946 (-52 G > A) at 5'UTR with the risk of common oral cavity pathologies that included periodontitis, caries, lichen planus, and recurrent aphthous stomatitis. Methods: The relevant studies were obtained by the two researchers from PubMed, Scopus, and Web of Science up to April 29, 2020. The manual search of the reference lists was also performed. Studies on DEFB1 gene polymorphisms and oral cavity disorders, using the case-control genetic association analysis approach, and published as full texts in English were included. To assess the association strength, odds ratios (ORs) with their 95% confidence intervals (CIs) were extracted. Results: Thirteen publications met the inclusion criteria and were incorporated in this meta-analysis. Statistically significant values of the association tests were found only for the rs1047031 polymorphism. Allele distribution in the rs1047031 polymorphism was significantly associated with susceptibility to oral cavity pathologies (adjusted P value = 0.003). The rare variant allele carriers had a significantly higher risk for oral disasters under recessive (CC vs CT + TT), and CC vs CT models. No significant correlations between rs11362, rs1800972, and rs1799946 and the risk of oral pathologies were revealed. Conclusions: Significant association between rs1047031 polymorphism and risk of oral pathologies has been found, and therefore, we suggest to include this polymorphism in future research concerning the genetic background of the oral cavity diseases.

Objective: Macrophages play an important part in the pathogenesis of osteoarthritis (OA). Our objective was to determine the effects of α-defensin-1 on macrophage polarization and consequently OA. Methods: OA synovial tissue and synovial fluid were assessed for the presence of M1 (CD68+CD16+CD206-) and M2 (CD68+CD206+CD16-) macrophages by flow cytometry. M0, M1, and M2 macrophages were co-cultured with OA chondrocytes to determine their influence on chondrogenic phenotype. Polarization of THP-1 activated monocytes from M1 to M2 in response to α-defensin-1 was evaluated by flow cytometry, RT-PCR and RNA sequencing. Effects of intra-articular α-defensin-1 in vivo were evaluated in a rat meniscal/ligamentous injury (MLI) model. Results: The quantity of M1 exceeded M2 polarized macrophages in human OA synovial tissue (mean difference 26.1% [13.6-38.6%], P < 0.001) and fluid (mean difference 10.5% [5.0-16.1%], P = 0.003). M1 to M2 polarization in vitro was most effectively promoted with 10 ng/mL α-defensin-1. Compared with untreated macrophages, the α-defensin-1 polarized macrophages modified co-cultured OA chondrocytes from a pro-catabolic state to a pro-anabolic (regenerative-like) state based on expression of COL2A1, ACN, MMP3, MMP13 and ADAMTS5. Intra-articular α-defensin-1 decreased severity of cartilage damage and synovitis in the MLI rat model. RNAseq analyses suggested insulin and Toll-like receptor signaling pathways in the chondroprotective α-defensin-1 mechanism of action. Conclusion: α-defensin-1 promotes M1 to M2 macrophage polarization in vitro, has beneficial effects on chondrocytes indirectly via M2 macrophage polarization, and attenuates the severity of OA in vivo, suggesting it might be a candidate treatment for OA.