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Can We Target Endogenous Anti-inflammatory Responses as a Therapeutic Strategy for Inflammatory Bowel Disease?

ABSTRACT: Inflammatory bowel disease (IBD) describes chronic relapsing remitting inflammation of the gastrointestinal tract including ulcerative colitis and Crohn's disease. The prevalence of IBD is rising across the globe. Despite a growing therapeutic arsenal, current medical treatments are not universally effective, do not induce lasting remission in all, or are accompanied by short- and long-term adverse effects. Therefore, there is a clinical need for novel therapeutic strategies for IBD. Current treatments for IBD mainly manipulate the immune system for therapeutic gain by inhibiting pro-inflammatory activity. There is a robust endogenous immunoregulatory capacity within the repertoire of both innate and adaptive immune responses. An alternative treatment strategy for IBD is to hijack and bolster this endogenous capability for therapeutic gain. This review explores this hypothesis and presents current evidence for this therapeutic direction in immune cell function, cytokine biology, and alternative mechanisms of immunoregulation such as microRNA, oligonucleotides, and the endocannabinoid system.

SUBMITTER: Porter RJ

PROVIDER: S-EPMC6140439 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Can We Target Endogenous Anti-inflammatory Responses as a Therapeutic Strategy for Inflammatory Bowel Disease?

Porter Ross John RJ Andrews Caroline C Brice Daniel Paul DP Durum Scott Kenneth SK McLean Mairi Hall MH

Inflammatory bowel diseases 20180901 10

Inflammatory bowel disease (IBD) describes chronic relapsing remitting inflammation of the gastrointestinal tract including ulcerative colitis and Crohn's disease. The prevalence of IBD is rising across the globe. Despite a growing therapeutic arsenal, current medical treatments are not universally effective, do not induce lasting remission in all, or are accompanied by short- and long-term adverse effects. Therefore, there is a clinical need for novel therapeutic strategies for IBD. Current tre ...[more]

PMID: 30020451

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Project description:BackgroundFormylated peptide receptor (FPR)-1 is a G-coupled receptor that senses foreign bacterial and host-derived mitochondrial formylated peptides (FPs), leading to innate immune system activation.AimWe sought to investigate the role of FPR1-mediated inflammation and its potential as a therapeutic target in inflammatory bowel disease (IBD).MethodsWe characterized FPR1 gene and protein expression in 8 human IBD (~1000 patients) datasets with analysis on disease subtype, mucosal inflammation, and drug response. We performed in vivo dextran-sulfate sodium (DSS) colitis in C57/BL6 FPR1 knockout mice. In ex vivo studies, we studied the role of mitochondrial FPs and pharmacological blockade of FPR1 using cyclosporin H in human peripheral blood neutrophils. Finally, we assess mitochondrial FPs as a potential mechanistic biomarker in the blood and stools of patients with IBD.ResultsDetailed in silico analysis in human intestinal biopsies showed that FPR1 is highly expressed in IBD (n = 207 IBD vs 67 non-IBD controls, P < .001), and highly correlated with gut inflammation in ulcerative colitis (UC) and Crohn's disease (CD) (both P < .001). FPR1 receptor is predominantly expressed in leukocytes, and we showed significantly higher FPR1+ve neutrophils in inflamed gut tissue section in IBD (17 CD and 24 UC; both P < .001). Further analysis in 6 independent IBD (data available under Gene Expression Omnibus accession numbers GSE59071, GSE206285, GSE73661, GSE16879, GSE92415, and GSE235970) showed an association with active gut inflammation and treatment resistance to infliximab, ustekinumab, and vedolizumab. FPR1 gene deletion is protective in murine DSS colitis with lower gut neutrophil inflammation. In the human ex vivo neutrophil system, mitochondrial FP, nicotinamide adenine dinucleotide dehydrogenase subunit-6 (ND6) is a potent activator of neutrophils resulting in higher CD62L shedding, CD63 expression, reactive oxygen species production, and chemotactic capacity; these effects are inhibited by cyclosporin H. We screened for mitochondrial ND6 in IBD (n = 54) using ELISA and detected ND6 in stools with median values of 2.2 gg/mL (interquartile range [IQR] 0.0-4.99; range 0-53.3) but not in blood. Stool ND6 levels, however, were not significantly correlated with paired stool calprotectin, C-reactive protein, and clinical IBD activity.ConclusionsOur data suggest that FPR1-mediated neutrophilic inflammation is a tractable target in IBD; however, further work is required to clarify the clinical utility of mitochondrial FPs as a potential mechanistic marker for future stratification.

Dataset Information

Can We Target Endogenous Anti-inflammatory Responses as a Therapeutic Strategy for Inflammatory Bowel Disease?

Publications

Can We Target Endogenous Anti-inflammatory Responses as a Therapeutic Strategy for Inflammatory Bowel Disease?

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