Browsing by Author "Holani, Ravi"

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    Immunomodulatory Role of Cathelicidin at Colonic Epithelium
    (2020-03-23) Holani, Ravi; Cobo, Eduardo R.; Proud, David; Barkema, Herman W.; Vogel, Hans J.
    Cathelicidin, a small, cationic and amphiphilic host defense peptide, is expressed by hematopoietic and non-hematopoietic cells. Initially considered an antimicrobial, cathelicidin are more than simply natural antibiotics. Due to their ability to interact with multiple receptors, cathelicidin can modulate immune responses by a variety of host cells. However, their immunomodulatory effects vary based on their micro-environment, including tissue type (hematopoietic vs. non-hematopoietic), availability of microbes or associated factor(s) and effective concentration of cathelicidin. Since most studies are performed in leukocytes, ability of cathelicidin to regulate immune responses by intestinal epithelium remains largely unknown. The objective was to elucidate immunomodulatory potential of cathelicidin in colonic epithelium, under homeostasis as well as during bacterial colitis. In the first study, we determined how cathelicidin synergized with lipopolysaccharide or Salmonella enterica Typhimurium to enhance production of neutrophil chemokine CXCL8 (human) or murine CXCL1 (functional homologue of CXCL8). Further, we identified a two-signal mechanism triggered by the complex of LPS-LL37, in which nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling was involved in CXCL8 mRNA synthesis, whereas p38 mitogen-activated protein kinase (p38MAPK) was involved in CXCL8 mRNA stabilization. In a Citrobacter rodentium model of colitis, we corroborated increased synthesis of CXCL1 chemokine, effective neutrophil recruitment and reduced bacterial burden in Camp+/+ versus Camp-/- (cathelicidin null) mice. In the second study, under physiological conditions, cathelicidin induced synthesis of Toll-like receptor (TLR) negative regulator, Toll-interacting protein (Tollip). This induced Tollip production inhibited TLR-mediated apoptosis in colonic epithelium, both in vitro by cytokines tumour necrosis factor- α and interferon- γ as well as in vivo in a C. rodentium model of colitis. In conclusion, cathelicidin regulated colonic innate immunity via reduction of unwarranted inflammation by inhibiting TLR responses through Tollip, while promoting a neutrophil response to infection.