Cathelicidin Antimicrobial Peptide: A Novel Regulator of Islet Function, Islet Regeneration, and Selected Gut Bacteria

Abstract

Cathelicidin antimicrobial peptide (CAMP) is a naturally occurring secreted peptide that is expressed in several organs with pleiotropic roles in immunomodulation, wound healing, and cell growth. We previously demonstrated that gut Camp expression is upregulated when type 1 diabetes–prone rats are protected from diabetes development. Unexpectedly, we have also identified novel CAMP expression in the pancreatic β-cells of rats, mice, and humans. CAMP was present even in sterile rat embryo islets, germ-free adult rat islets, and neogenic tubular complexes. Camp gene expression was downregulated in young BBdp rat islets before the onset of insulitis compared with control BBc rats. CAMP treatment of dispersed islets resulted in a significant increase in intracellular calcium mobilization, an effect that was both delayed and blunted in the absence of extracellular calcium. Additionally, CAMP treatment promoted insulin and glucagon secretion from isolated rat islets. Thus, CAMP is a promoter of islet paracrine signaling that enhances islet function and glucoregulation. Finally, daily treatment with the CAMP/LL-37 peptide in vivo in BBdp rats resulted in enhanced β-cell neogenesis and upregulation of potentially beneficial gut microbes. In particular, CAMP/LL-37 treatment shifted the abundance of specific bacterial populations, mitigating the gut dysbiosis observed in the BBdp rat. Taken together, these findings indicate a novel functional role for CAMP/LL-37 in islet biology and modification of gut microbiota.

Serum cathelicidin, nasopharyngeal microbiota, and disease severity among infants hospitalized with bronchiolitis

“…Recent studies are beginning to delineate the mechanisms, by which innate immune systems interact with microbes in non-respiratory niches, such as the gastrointestinal tract. 7 The current study demonstrates, for the first time, an integrated role of LL-37 antimicrobial peptides (an important component of the innate immune system) and the airway microbiota in the pathogenesis of airway disease. Our data should facilitate further mechanistic investigations into this complex interplay.…”

“…5 In prior studies, serum cathelicidin level was inversely associated with disease severity in children with bronchiolitis, 6 and administration of LL-37 (the main active form of human cathelicidin) altered the microbiota in animal models. 7 We have previously demonstrated that, in a cohort of infants with severe bronchiolitis (bronchiolitis requiring hospitalization), 4 infants with a Haemophilus -dominant nasopharyngeal microbiota profile had higher severity; however, host immune responses were not examined. In the present study, we sought to determine interactions between serum LL-37 levels and nasopharyngeal microbiota profiles with regard to disease severity by using the data from a prospective cohort of infants with severe bronchiolitis.…”

Replicative capacity of β-cells and type 1 diabetes

“…Recent experiments suggest that M2 macrophages can prevent the onset of inflammatory response in T1D; such protection is likely mediated by secreted peptides with pro-proliferative, anti-inflammatory effects [57]. In particular, several studies focused on the heme oxygenase-1 (HO-1) pathway, whose induction confers protection from oxidative damage [58] and reduces the incidence of T1D in the BioBreeding diabetes-prone (BBdp) rat model [59–61].…”

Immunomodulatory effects of anti-microbial peptides

“…In addition, the expression of TLR4 and CD14 is increased on LL-37-treated macrophages. Daily treatment of an inbred laboratory rat strain that spontaneously develops autoimmune type-1 diabetes with LL-37 results in enhanced β-cell neogenesis and upregulation of beneficial gut microbes [80]. In general, by inducing migration of neutrophils, monocytes and macrophages, eosinophils, and mast cells as well as prolonging the lifespan of neutrophils, cathelicidins directly modulate epithelial cell and keratinocyte responses to infecting pathogens [81].…”