Cathelicidin modulates synthesis of Toll-like Receptors (TLRs) 4 and 9 in colonic epithelium

Marin, Maia Solange; Holani, Ravi; Shah, Chaitanya; Odeón, Anselmo; Cobo, Eduardo R.

doi:10.1016/j.molimm.2017.09.011

Cited by 18 publications

(17 citation statements)

References 41 publications

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“…71,72 Also, CXCL8 mRNA synthesis was reduced by LL-37+ oligodinucelotide in colonic epithelial cells. 40 Furthermore, in murine macrophages, LPS-containing outer membrane vesicles shed by C. rodentium were endocytosed, which then activated caspase-11 and mediated cell death. 73 We did not observe caspase-11 activation and/or cytotoxicity in colonic epithelium after LPS+LL-37 treatment, suggesting LL-37 is particularly involved in signaling via endosomal TLR4 and secreting CXCL1 chemokine in colonic epithelium.…”

Section: Discussionmentioning

confidence: 99%

“…or E. coli. 40,41 Herein, there was a key role of colonic epithelial TLR4 for cathelicidin-induced CXCL8 secretion. Inhibition of TLR4 with LPS-RS blocked CXCL8 mRNA and protein synthesis in HT29 cells challenged with LPS+LL-37 ( Figure 4a-b).…”

Section: Lps and Ll-37 Through Extracellular Interaction Induced Cxclmentioning

confidence: 99%

“…Cells were pre-treated (or not) for 1 h with inhibitors at concentrations either based on their IC 50 values as recommended by manufacturer(s) or obtained from previous studies and maintained in culture medium without FBS or antibiotics. 40,47,96 Activation/phosphorylation of signal components (p38MAPK, ERK1/2 and NF-κB) was monitored by western blot analysis. Total proteins from cell lysates were isolated using DCEB buffer with a protease inhibitor cocktail.…”

Section: Signal Transduction Pathwaysmentioning

confidence: 99%

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Cathelicidin-mediated lipopolysaccharide signaling via intracellular TLR4 in colonic epithelial cells evokes CXCL8 production

et al. 2020

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We hypothesized that the antimicrobial peptide cathelicidin has a physiological role in regulating gut inflammatory homeostasis. We determined that cathelicidin synergizes with LPS to facilitate its internalization and signaling via endosomic TLR4 in colonic epithelium, evoking synthesis of the human neutrophil chemoattractant, CXCL8 (or murine homolog, CXCL1). Interaction of cathelicidin with LPS in the control of CXCL8/CXCL1 synthesis was assessed in human colon epithelial cells, murine colonoids and cathelicidin-null mice (Camp −/-). Mechanistically, human cathelicidin (LL-37), as an extracellular complex with LPS, interacted with lipid raft-associated GM1 gangliosides to internalize and activate intracellular TLR4. Two signaling pathways converged on CXCL8/CXCL1 production: (1) a p38MAPK-dependent pathway regulated by Src-EGFR kinases; and, (2) a p38MAPKindependent, NF-κB-dependent pathway, regulated by MEK1/2-MAPK. Increased cathelicidindependent CXCL8 secretion in the colonic mucosa activated human blood-derived neutrophils. These cathelicidin effects occurred in vitro at concentrations well below those needed for microbicidal function. The important immunomodulatory role of cathelicidins was evident in cathelicidinnull/Camp −/mice, which had diminished colonic CXCL1 secretion, decreased neutrophil recruitment-activation and reduced bacterial clearance when challenged with the colitis-inducing murine pathogen, Citrobacter rodentium. We conclude that in addition to its known microbicidal action, cathelicidin has a unique pathogen-sensing role, facilitating LPS-mediated intestinal responses, including the production of CXCL8/CXCL1 that would contribute to an integrated tissue response to recruit neutrophils during colitis.

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Section: Discussionmentioning

confidence: 99%

Section: Lps and Ll-37 Through Extracellular Interaction Induced Cxclmentioning

confidence: 99%

Section: Signal Transduction Pathwaysmentioning

confidence: 99%

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Cathelicidin-mediated lipopolysaccharide signaling via intracellular TLR4 in colonic epithelial cells evokes CXCL8 production

et al. 2020

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“…A first role of cathelicidins in gut innate immuninty could be enhancement of Toll-like receptor (TLR) sensing and prevention of pathogen invasion into colonic epithelial cells. For instance, human adenocarcinoma colonic epithelial (HT-29) cells exposed to a combination of synthetic LL-37 and LPS had increased TLR4 gene and protein expression (13). Such TLR4 activation is expected to increase production of pro-inflammatory cytokines, since LL-37 was required for CXCL8 and IL-1β production from colonocytes exposed to bacterial stimuli (13,14).…”

Section: Cathelicidinsmentioning

confidence: 99%

“…For instance, human adenocarcinoma colonic epithelial (HT-29) cells exposed to a combination of synthetic LL-37 and LPS had increased TLR4 gene and protein expression (13). Such TLR4 activation is expected to increase production of pro-inflammatory cytokines, since LL-37 was required for CXCL8 and IL-1β production from colonocytes exposed to bacterial stimuli (13,14). Moreover, the combination of cathelicidin and LPS prevented invasion of Salmonella enterica serovar Typhimurium into HT-29 cells (14).…”

Section: Cathelicidinsmentioning

confidence: 99%

The Network of Colonic Host Defense Peptides as an Innate Immune Defense Against Enteropathogenic Bacteria

et al. 2020

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Host defense peptides, abundantly secreted by colonic epithelial cells and leukocytes, are proposed to be critical components of an innate immune response in the colon against enteropathogenic bacteria, including Shigella spp., Salmonella spp., Clostridium difficile, and attaching and effacing Escherichia coli and Citrobacter rodentium. These short cationic peptides are bactericidal against both Gram-positive and-negative enteric pathogens, but may also exert killing effects on intestinal luminal microbiota. Simultaneously, these peptides modulate numerous cellular responses crucial for gut defenses, including leukocyte chemotaxis and migration, wound healing, cytokine production, cell proliferation, and pathogen sensing. This review discusses recent advances in our understanding of expression, mechanisms of action and microbicidal and immunomodulatory functions of major colonic host defense peptides, namely cathelicidins, β-defensins, and members of the Regenerating islet-derived protein III (RegIII) and Resistin-like molecule (RELM) families. In a theoretical framework where these peptides work synergistically, aspects of pathogenesis of infectious colitis reviewed herein uncover roles of host defense peptides aimed to promote epithelial defenses and prevent pathogen colonization, mediated through a combination of direct antimicrobial function and fine-tuning of host immune response and inflammation. This interactive host defense peptide network may decode how the intestinal immune system functions to quickly clear infections, restore homeostasis and avoid damaging inflammation associated with pathogen persistence during infectious colitis. This information is of interest in development of host defense peptides (either alone or in combination with reduced doses of antibiotics) as antimicrobial and immunomodulatory therapeutics for controlling infectious colitis.

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Human cathelicidin improves colonic epithelial defenses against Salmonella typhimurium by modulating bacterial invasion, TLR4 and pro-inflammatory cytokines

et al. 2019

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Cathelicidin modulates synthesis of Toll-like Receptors (TLRs) 4 and 9 in colonic epithelium

Cited by 18 publications

References 41 publications

Cathelicidin-mediated lipopolysaccharide signaling via intracellular TLR4 in colonic epithelial cells evokes CXCL8 production

Cathelicidin-mediated lipopolysaccharide signaling via intracellular TLR4 in colonic epithelial cells evokes CXCL8 production

The Network of Colonic Host Defense Peptides as an Innate Immune Defense Against Enteropathogenic Bacteria

Human cathelicidin improves colonic epithelial defenses against Salmonella typhimurium by modulating bacterial invasion, TLR4 and pro-inflammatory cytokines

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