IL-23–responsive innate lymphoid cells are increased in inflammatory bowel disease

Geremia, A; Arancibia‐Cárcamo, Carolina V.; Fleming, Myles; Rust, Nigel; Singh, Baljit; Mortensen, Neil; Travis, Simon; Powrie, Fiona

doi:10.1084/jem.20101712

Cited by 578 publications

(534 citation statements)

References 32 publications

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“…2). Functional studies with genetically engineered animals and IL 23 p19 and p40 blockers suggested that blockade of these cytokine subunits might effectively suppress intestinal inflammation in mouse models of colitis [98][99][100][101][102][103][104] . In particular, IL 23 inhibition was effective and prevented activation of T cells and innate lymphoid cells and tissue destruction in vivo.…”

Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

528

403

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Inflammatory bowel diseases (including IBD, exempli fied by Crohn's disease and ulcerative colitis) are chronic relapsing disorders affecting the gastrointestinal tract. IBD has a progressive and destructive nature and, there fore, can cause various complications including steno ses, abscesses, fistulas, extraintestinal manifestations and colitis associated neoplasias and cancer 1,2 . Thus, effective therapeutic approaches are of high clinical rele vance in patients with IBD. This Review summarizes current therapeutic strategies and highlights emerging new treatment approaches for IBD with special refer ence to the proposed molecular mechanisms of action of anti inflammatory drugs. Current IBD therapiesClassic anti-inflammatory drugs. 5 Aminosalicylates (5 ASAs) are important anti inflammatory drugs that are frequently used for anti inflammatory therapy in patients with ulcerative colitis 3 . By contrast, 5 ASA based drugs show little or no efficacy in inducing res olution of clinical symptoms and tissue inflammation in patients with Crohn's disease 4 .5 ASAs are effective for induction and mainten ance of remission in ulcerative colitis and might also reduce the risk of developing colitis associated tumours in these patients 5 . Several mechanisms of action for 5 ASAs have been proposed, including reduction of prostaglandin synthesis via inhibition of cyclooxygenase, suppression of proinflammatory cytokine production and oxygen free radicals, inhib ition of lipoxygenase, blockade of neutrophil chemo taxis and mast cell activation, and impairment of nuclear factor κB activation (NF κB) in immune cells 3 . Moreover, studies in mice revealed that 5 ASA based drugs augment peroxisome proliferator activated receptor γ (PPARγ) expression and promote PPARγ translocation from the cytoplasm to the nucleus where they result in activation of peroxisome proliferator hormone response element driven genes to suppress colitis activity 6,7 .In addition to 5 ASAs, corticosteroids (systemically or topically delivered) have been used for remission induction in ulcerative colitis 2 . Although cortico steroids favour induction of remission in both ulcer ative colitis and Crohn's disease, they are not suitable for mainten ance of remission in IBD 1,2 . Mechanistically, gluco corticoids bind to a specific cytosolic receptor fol lowed by translocation of the complex to the nucleus to either activate or repress gene transcription (via bind ing to DNA corticosteroid response elements) 8,9 . Additionally, the glucocorticoid-receptor complex can inactivate pro inflammatory transcription factors such as NF κB and activator protein 1 (AP1) via proteinprotein inter actions, thereby preventing their activation of inflammatory mediators (for example, leukotrienes and cytokines such as IL 1 and IL 6). REVIEWS© 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

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Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

528

403

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“…In response to IL-23, DCs produce great amounts of IL-6, which activates other innate cells that may mediate tissue destruction (72). In addition, IL-23 stimulates innate lymphoid cells (ILCs) to secrete IL-17, IL-22, and IFN-γ in human colitis (73) and mouse colitis (71). Thus, Opn may contribute to innate colitis via induction of IL-23 in DCs and/or other innate cells.…”

Section: Discussionmentioning

confidence: 99%

Osteopontin expression by CD103⁻dendritic cells drives intestinal inflammation

Kourepini

Aggelakopoulou

Alissafi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Intestinal CD103 − dendritic cells (DCs) are pathogenic for colitis. Unveiling molecular mechanisms that render these cells proinflammatory is important for the design of specific immunotherapies. In this report, we demonstrated that mesenteric lymph node CD103 − DCs express, among other proinflammatory cytokines, high levels of osteopontin (Opn) during experimental colitis. Opn expression by CD103 − DCs was crucial for their immune profile and pathogenicity, including induction of T helper (Th) 1 and Th17 cell responses. Adoptive transfer of Opn-deficient CD103 − DCs resulted in attenuated colitis in comparison to transfer of WT CD103 − DCs, whereas transgenic CD103 − DCs that overexpress Opn were highly pathogenic in vivo. Neutralization of secreted Opn expressed exclusively by CD103 − DCs restrained disease severity. Also, Opn deficiency resulted in milder disease, whereas systemic neutralization of secreted Opn was therapeutic. We determined a specific domain of the Opn protein responsible for its CD103 − DC-mediated proinflammatory effect. We demonstrated that disrupting the interaction of this Opn domain with integrin α9, overexpressed on colitic CD103 − DCs, suppressed the inflammatory potential of these cells in vitro and in vivo. These results add unique insight into the biology of CD103 − DCs and their function during inflammatory bowel disease.

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“…Neonatal ILC3 can also mediate intestinal pathology in response to transgenic over‐expression of IL‐23 through the release of IL‐17A, IL‐22, IFN‐ γ and GM‐CSF 130. In line with a disease‐causing role of ILC3, Crohn's disease patients exhibit increased frequency of NCR − (NKp44 − CD56 − ) CCR6 + ILC3 and have elevated levels of IL‐17A 131. Hence, in contrast to their protective and homeostatic roles, ILC3 may also take on pro‐inflammatory roles and contribute to tissue damage and inflammation during disease.…”

Section: Ilc3 In Inflammation and Infectionmentioning

confidence: 99%

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

2017

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SummaryGroup 3 innate lymphoid cells (ILC3), defined by expression of the transcription factor retinoid‐related orphan receptor γt, play key roles in the regulation of inflammation and immunity in the gastrointestinal tract and associated lymphoid tissues. ILC3 consist largely of two major subsets, NCR + ILC3 and LTi‐like ILC3, but also demonstrate significant plasticity and heterogeneity. Recent advances have begun to dissect the relationship between ILC3 subsets and to define distinct functional states within the intestinal tissue microenvironment. In this review we discuss the ever‐expanding roles of ILC3 in the context of intestinal homeostasis, infection and inflammation – with a focus on comparing and contrasting the relative contributions of ILC3 subsets.

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IL-23–responsive innate lymphoid cells are increased in inflammatory bowel disease

Abstract: Increased numbers of innate lymphoid cells in patients with inflammatory bowel disease.

Cited by 578 publications

References 32 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

Osteopontin expression by CD103⁻dendritic cells drives intestinal inflammation

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

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IL-23–responsive innate lymphoid cells are increased in inflammatory bowel disease

Abstract: Increased numbers of innate lymphoid cells in patients with inflammatory bowel disease.

Cited by 578 publications

References 32 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

Osteopontin expression by CD103−dendritic cells drives intestinal inflammation

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

Contact Info

Product

Resources

About

Osteopontin expression by CD103⁻dendritic cells drives intestinal inflammation