Human β-Defensin 2 Mediated Immune Modulation as Treatment for Experimental Colitis

Abstract

Defensins represents an integral part of the innate immune system serving to ward off potential pathogens and to protect the intestinal barrier from microbial encroachment. In addition to their antimicrobial activities, defensins in general, and human β-defensin 2 (hBD2) in particular, also exhibit immunomodulatory capabilities. In this report, we assessed the therapeutic efficacy of systemically administered recombinant hBD2 to ameliorate intestinal inflammation in three distinct animal models of inflammatory bowel disease; i.e., chemically induced mucosal injury (DSS), loss of mucosal tolerance (TNBS), and T-cell transfer into immunodeficient recipient mice. Treatment efficacy was confirmed in all tested models, where systemically administered hBD2 mitigated inflammation, improved disease activity index, and hindered colitis-induced body weight loss on par with anti-TNF-α and steroids. Treatment of lipopolysaccharide (LPS)-activated human peripheral blood mononuclear cells with rhBD2 confirmed the immunomodulatory capacity in the circulatory compartment. Subsequent analyzes revealed dendritic cells (DCs) as the main target population. Suppression of LPS-induced inflammation was dependent on chemokine receptor 2 (CCR2) expression. Mechanistically, hBD2 engaged with CCR2 on its DC target cell to decrease NF-κB, and increase CREB phosphorylation, hence curbing inflammation. To our knowledge, this is the first study showing in vivo efficacy of a systemically administered defensin in experimental disease.

The Dichotomous Responses Driven by β-Defensins

“…The effect was lost in the presence of a CCR2 inhibitor. When HBD2 was delivered systemically to a variety of mouse models of inflammatory bowel disease, the colitis was reduced to a level comparable to steroids and anti-TNFα (90). In addition, in the infected cornea of mice, silencing of the murine orthologues of HBD2 and 3 resulted in increased production of proinflammatory cytokines, with a simultaneous increase in bacterial load (91).…”

“…Patients who suffer from Crohn's disease present a decrease in HBD2 β-defensin levels, and a concomitant decrease in the gene copy repeating unit suggested as a factor for predisposition to the disease (133,134). HBD2 has recently been delivered subcutaneously to mice with induced models of intestinal bowel disease and successfully reduced the level of inflammation (90). In opposition to Crohn's disease, patients with ulcerative colitis (a disease of the colon) have a highly increased expression of HBD2, although not HBD1 (135).…”

An Update Review on the Paneth Cell as Key to Ileal Crohn's Disease

“…Future studies on the regulatory network of Paneth cells, maybe like those reported recently, using transcriptomics approaches may delineate additional complexity in these already remarkably versatile cells (114). Finally, and this is what counts for the patients: if the chance to substitute for mucosal defensins by systemic or oral administration, as mentioned above, really works out, this originally unlikely hypothesis may lead to a promising new therapy both in Crohn's disease (115,116) as well as in intestinal graft vs. host disease (117)…”

Plant Antimicrobial Peptides: State of the Art, In Silico Prediction and Perspectives in the Omics Era

“…For example, human alpha-and beta-defensins present in the saliva may potentially impede virus replication, including SARS-CoV-2, 8 besides other roles as protection against intestinal inflammation (colitis). 9 Considering the roles of plant peptides, they can also be multifunctional, and have been classified into 2 main categories 10 (Supplementary Figure S1): (1) Peptides with no bioactivity, primarily resulting from the degradation of proteins by proteolytic enzymes, aiming at their recycling, and (2) bioactive peptides, which are encrypted in the structure of the parent proteins and are released mainly by enzymatic processes.…”

“…For example, human alpha- and beta-defensins present in the saliva may potentially impede virus replication, including SARS-CoV-2, 8 besides other roles as protection against intestinal inflammation (colitis). 9 …”