Homeostatic IL-23 receptor signaling limits Th17 response through IL-22–mediated containment of commensal microbiota

Shih, Vincent Feng-Sheng; Cox, Jennifer H.; Kljavin, Noelyn M.; Dengler, Hart S.; Reichelt, Mike; Kumar, Perikala V.; Rangell, Linda; Kolls, Jay K.; Diehl, Lauri; Ouyang, Wenjun; Ghilardi, Nico

doi:10.1073/pnas.1323852111

Cited by 88 publications

(91 citation statements)

References 28 publications

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“…Further, we demonstrated that CF and WT mouse T lymphocytes produce IL-17 in response to IL-23 in a dose-dependent fashion, with CF mouse lymphocytes being particularly sensitive to IL-23 stimulation. This suggests T-cell dysregulation in CF, which is consistent with information published in the literature (6,42). The studies with…”

Section: Discussionsupporting

confidence: 91%

Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation

et al. 2016

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c Cystic fibrosis (CF) is characterized by an excessive neutrophilic inflammatory response within the airway as a result of defective cystic fibrosis transmembrane receptor (CFTR) expression and function. Interleukin-17A induces airway neutrophilia and mucin production associated with Pseudomonas aeruginosa colonization, which is associated with the pathophysiology of cystic fibrosis. The objectives of this study were to use the preclinical murine model of cystic fibrosis lung infection and inflammation to investigate the role of IL-17 in CF lung pathophysiology and explore therapeutic intervention with a focus on IL-17. Cftr-deficient mice (CF mice) and wild-type mice (WT mice) infected with P. aeruginosa had robust IL-17 production early in the infection associated with a persistent elevated inflammatory response. Intratracheal administration of IL-17 provoked a neutrophilic response in the airways of WT and CF animals which was similar to that observed with P. aeruginosa infection. The neutralization of IL-17 prior to infection significantly improved the outcomes in the CF mice, suggesting that IL-17 may be a therapeutic target. We demonstrate in this report that the pathophysiological contribution of IL-17 may be due to the induction of chemokines from the epithelium which is augmented by a deficiency of Cftr and ongoing inflammation. These studies demonstrate the in vivo contribution of IL-17 in cystic fibrosis lung disease and the therapeutic validity of attenuating IL-17 activity in cystic fibrosis. Cystic fibrosis (CF) lung disease is characterized by an exaggerated inflammatory response associated with the robust infiltration of neutrophils within the airways (1, 2). The etiology of this excessive inflammation remains to be elucidated. Many cytokines and small molecules have been shown to recruit neutrophils into the airway of individuals with CF, including interleukin-8 (IL-8) and leukotriene (LT) B4 (3-7). IL-17 has traditionally been identified to be a product of activated T lymphocytes and is critically important in the host lung response to infections caused by Gram-negative bacteria, including Pseudomonas aeruginosa (8,9). Experiments with IL-17 receptor knockout (KO) mice have demonstrated an increased susceptibility to Gram-negative bacterial pneumonia due to excessive neutrophil recruitment into the airways (10-13) and the upregulation of airway mucins, potentially contributing to inefficient mucociliary clearance (5,14).Increased concentrations of IL-17 have been associated with a wide range of inflammatory diseases, including rheumatoid arthritis (15, 16), inflammatory bowel disease (17), diabetes (18,19), cancer (20), and allergic asthma (21, 22). The utilization of neutralizing IL-17A antibodies in a mouse model of allergic asthma (23, 24) and lipopolysaccharide-induced inflammation (9, 25) demonstrated decreased airway neutrophilia, implicating IL-17 as a potential therapeutic target in asthma. IL-17 has also been associated with P. aeruginosa infections, linking it to not just the patholo...

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Section: Discussionsupporting

confidence: 91%

Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation

et al. 2016

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“…Mice with disrupted ILC3‐derived IL‐22 responses exhibit altered gut microbiota and increased susceptibility to experimentally induced colitis 49, 80, 81, 82. Most notably, expansion of segmented filamentous bacteria (SFB) – a canonical Th17‐inducing commensal species – occurs in the absence of ILC3 responses 49.…”

Section: Ilc3 Functions Under Homeostatic Conditionsmentioning

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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“…Mice lacking Ahr, IL-22, IL-23p19, or IL-23R have relative outgrowth of SFB and increased intestinal Th17 cells, and this appears to be due to a marked decrease in IL-22-producing immune cells, particularly ILC3s (92)(93)(94). IL-22 is critical for maintaining intestinal barrier function, and in the absence of IL-22, SFB increase in relative abundance, leading to an increased may lead to altered immune responses and promote autoimmunity.…”

Section: Il-23 and Autoimmunitymentioning

confidence: 99%

“…This appears to be directly mediated by the salt-sensitive kinase, frequency of Th17 cells in both the intestine and distal secondary lymphoid tissue (93,95,96). IL-23-induced IL-22 also appears to be critical for prohibiting microbiota from entering normally restricted anatomical compartments, as mice deficient in both IL-23R and RAG2 have elevated levels of LPS in both the spleen and liver (93). Furthermore, selective depletion of ILCs results in systemic dissemination of Alcaligenes spp., a normal enteric commensal (97).…”

Section: Il-23 and Autoimmunitymentioning

confidence: 99%

“…In addition to fats, processed foods are also rich in salt, and recent work has shown that a diet high in salt may promote both Th17 differentiation and induction of autoimmunity (54, 55). This appears to be directly mediated by the salt-sensitive kinase, frequency of Th17 cells in both the intestine and distal secondary lymphoid tissue (93,95,96). IL-23-induced IL-22 also appears to be critical for prohibiting microbiota from entering normally restricted anatomical compartments, as mice deficient in both IL-23R and RAG2 have elevated levels of LPS in both the spleen and liver (93).…”

mentioning

confidence: 99%

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Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity

Burkett¹,

Hörste²,

Kuchroo³

2015

J. Clin. Invest.

196

135

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R e v i e w S e R i e S : A u t o i m m u n i t y2 2 1 2 jci.org Volume 125 Number 6 June 2015Murine Th17 differentiation can also be induced in the absence of TGF-β1 signaling, via the combination either of IL-1β, IL-6, and IL-23 or of 42). These TGF-β1-independent Th17 cells can efficiently induce autoimmune tissue inflammation upon adoptive transfer, a trait that led to them being termed "pathogenic" Th17 cells. Additionally, they possess a gene expression profile distinct from that of "nonpathogenic" Th17 cells, which are differentiated with TGF-β1 and IL-6. These observations have led to two competing hypotheses. The first posits that IL-23 cements Th17 lineage commitment such that Th17 cells induced with TGF-β1 and IL-6 are insufficiently committed to the lineage and cannot induce autoimmune tissue inflammation. The second suggests that there are distinct subtypes of Th17 cells whose differentiation is dependent on distinct combinations of cytokines. The latter hypothesis is supported by the finding that pathogenic Th17 cells express higher levels of several Th1 lineage-associated transcripts, such as the transcription factor T-bet and IFN-γ, and have been shown to be derived from IL-17 single producers by fate mapping experiments (43,44). Similarly, an important feature of human Th17 cells, as well as those isolated from inflamed tissues in mouse models of Th17-mediated disease, is that they coproduce IL-17 with other cytokines, leading to distinct functional roles (45)(46)(47). For instance, human Th17 cells that produce both IL-10 and IL-17 preferentially respond to Staphylococcus aureus, while those that produce both IL-17 and IFN-γ recognize Candida albicans, suggesting that distinct pathogens induce distinct subtypes of Th17 cells (40). IL-17/IFN-γ coproducers have been ascribed pathogenic functions in the CNS during EAE; however, it has been difficult to reliably differentiate such cells in vitro. Repeated rounds of in vitro culture in the presence of either Th1-inducing cytokines or IL-23 can induce IL-17/IFN-γ coproducers, albeit at moderate percentages. The transcription factors T-bet, RUNX1, and RUNX3 appear to be important in the acquisition of this phenotype (48,49).Large-scale transcriptional analysis of Th17 differentiation at very high temporal resolution has begun to elucidate the molecular networks that control this process, and is a promising approach to the identification of novel regulatory molecules that control pathogenic Th17 differentiation (50, 51). In fact, Th17 development is controlled induction of this lineage. The combination of TGF-β1 and IL-6 efficiently induces IL-17-producing murine T cells in vitro and highlights the reciprocal relationship between induced Tregs, which are generated by TGF-β1 alone, and Th17 cells (19,20). A series of studies demonstrated that IL-21, a γ c -dependent cytokine, could promote the differentiation of Th17 cells (21-23). In combination with TGF-β, IL-21 induces IL-17 production from naive Th cells and promotes the expression of both RORγt, th...

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Homeostatic IL-23 receptor signaling limits Th17 response through IL-22–mediated containment of commensal microbiota

Cited by 88 publications

References 28 publications

Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation

Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity

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