Targeting IL-22 and IL-22R protects against experimental osteoarthritis.
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ABSTRACT:
SUBMITTER: Yi C
PROVIDER: S-EPMC8093291 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cutaneous leishmaniasis is a disease characterized by ulcerating skin lesions, the resolution of which requires an effective, but regulated, immune response that limits parasite growth without causing permanent tissue damage. While mechanisms that control the parasites have been well studied, the factors regulating immunopathologic responses are less well understood. IL-22, a member of the IL-10 family of cytokines, can contribute to wound healing, but in other instances promotes pathology. Here we investigated the role of IL-22 during leishmania infection, and found that IL-22 limits leishmania-induced pathology when a certain threshold of damage is induced by a high dose of parasites. Il22-/- mice developed more severe disease than wild-type mice, with significantly more pathology at the site of infection, and in some cases permanent loss of tissue. The increased inflammation was not due to an increased parasite burden, but rather was associated with the loss of a wound healing phenotype in keratinocytes. Taken together, these studies demonstrate that during cutaneous leishmaniasis, IL-22 can play a previously unappreciated role in controlling leishmania-induced immunopathology.
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Project description:Diabetic foot ulcers (DFU) are one of the major complications in type II diabetes patients and can result in amputation and morbidity. Although multiple approaches are used clinically to help wound closure, many patients still lack adequate treatment. Here we show that IL-20 subfamily cytokines are upregulated during normal wound healing. While there is a redundant role for each individual cytokine in this subfamily in wound healing, mice deficient in IL-22R, the common receptor chain for IL-20, IL-22, and IL-24, display a significant delay in wound healing. Furthermore, IL-20, IL-22 and IL-24 are all able to promote wound healing in type II diabetic db/db mice. Mechanistically, when compared to other growth factors such as VEGF and PDGF that accelerate wound healing in this model, IL-22 uniquely induced genes involved in reepithelialization, tissue remodeling and innate host defense mechanisms from wounded skin. Interestingly, IL-22 treatment showed superior efficacy compared to PDGF or VEGF in an infectious diabetic wound model. Taken together, our data suggest that IL-20 subfamily cytokines, particularly IL-20, IL-22, and IL-24, might provide therapeutic benefit for patients with DFU.
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Project description:Interleukin (IL)-22, an immune cell-derived cytokine whose receptor expression is restricted to non-immune cells (e.g. epithelial cells), can be anti-inflammatory and pro-inflammatory. Mice infected with the tapeworm Hymenolepis diminuta are protected from dinitrobenzene sulphonic acid (DNBS)-induced colitis. Here we assessed expulsion of H. diminuta, the concomitant immune response and the outcome of DNBS-induced colitis in wild-type (WT) and IL-22 deficient mice (IL-22-/-) ± infection. Interleukin-22-/- mice had a mildly impaired ability to expel the worm and this correlated with reduced or delayed induction of TH2 immunity as measured by splenic and mesenteric lymph node production of IL-4, IL-5 and IL-13 and intestinal Muc-2 mRNA and goblet cell hyperplasia; in contrast, IL-25 increased in the small intestine of IL-22-/- mice 8 and 12 days post-infection compared to WT mice. In vitro experiments revealed that H. diminuta directly evoked epithelial production of IL-25 that was inhibited by recombinant IL-22. Also, IL-10 and markers of regulatory T cells were increased in IL-22-/- mice that displayed less DNBS (3 mg, ir. 72h)-induced colitis. Wild-type mice infected with H. diminuta were protected from colitis, as were infected IL-22-/- mice and the latter to a degree that they were almost indistinguishable from control, non-DNBS treated mice. Finally, treatment with anti-IL-25 antibodies exaggerated DNBS-induced colitis in IL-22-/- mice and blocked the anti-colitic effect of infection with H. diminuta. Thus, IL-22 is identified as an endogenous brake on helminth-elicited TH2 immunity, reducing the efficacy of expulsion of H. diminuta and limiting the effectiveness of the anti-colitic events mobilized following infection with H. diminuta in a non-permissive host.
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Project description:Interleukin 18 (IL-18) promotes inflammation and apoptosis in chondrocytes, thereby contributing to the development and progression of osteoarthritis (OA). Here, we investigated the effects of IL-18 treatment and inhibition in rat chondrocytes in vitro and in vivo. We used RT-PCR and Western blotting to measure the mRNA and protein levels of the chondrocyte-specific genes Collagen II and Aggrecan as well as the protein levels of apoptosis-related (Bax, Bcl2, Caspase3/9), autophagy-related (Atg5, Atg7, Beclin1, LC3), and mTOR pathway-related genes (PI3K, Akt, mTOR). We observed a decrease in Collagen II and Aggrecan mRNA and protein levels, upregulation of chondrocyte apoptosis, downregulation of chondrocyte autophagy, and activation of the PI3K/Akt/mTOR pathway upon IL-18 treatment. PI3K/Akt/mTOR pathway activation and inhibition tests using rat 740Y-P (PI3K activator), SC79 (AKT activator), 3BDO (mTOR activator), or LY294002 (PI3K inhibitor) revealed that activation of the PI3K/Akt/mTOR pathway enhances chondrocyte-specific gene degradation induced by IL-18, while its inhibition has protective effects on chondrocytes. We also found that treatment with rapamycin (a selective mTOR inhibitor) also exerts chondro-protective effects that ameliorate OA by promoting autophagy. These results suggest that inhibition of the mTOR pathway could be exploited for therapeutic benefits in the treatment of OA.
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Project description:The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, Gclc deficiency did not alter cytokine secretion; however, C. rodentium infection induced increased ROS and disrupted mitochondrial function and TFAM-driven mitochondrial gene expression, resulting in decreased cellular ATP. These changes impaired the PI3K/AKT/mTOR pathway, reducing phosphorylation of 4E-BP1 and consequently limiting IL-22 translation. The resultant low IL-22 levels led to poor bacterial clearance, severe intestinal damage, and high mortality. Our findings highlight a previously unrecognized, essential role of Th17 cell-intrinsic GSH in promoting mitochondrial function and cellular signaling for IL-22 protein synthesis, which is critical for intestinal integrity and defense against gastrointestinal infections.
2024-07-01 | GSE248348 | GEO
Project description:Histone deacetylases are key epigenetic regulators that control T cell-mediated immunity. A T cell-specific deletion of Hdac1 (HDAC1cKO) protects mice against experimental autoimmune encephalomyelitis (EAE). However, it remains elusive whether inhibition of HDAC1 enzymatic activity and thus mimicking HDAC1 inhibitor treatment is sufficient to block EAE induction. In order to address this question, we generated a novel mouse strain that expresses catalytically inactive HDAC1 (HDAC1Off) from the Rosa26 locus in HDAC1cKO CD4+ T cells to mimic selective inhibition of HDAC1 enzymatic activity in vivo. Mice expressing wildtype HDAC1 in HDAC1cKO CD4+ T cells (HDAC1On) were generated as corresponding controls. In contrast to HDAC1On mice, HDAC1Off mice did not develop EAE, and this correlated with diminished leukocyte CNS infiltration. HDAC1Off CD4+ T cells in the CNS displayed a severe reduction of IFNγ, IL-17A and TNFα proinflammatory cytokine expression. In vivo activated HDAC1Off CD4+ T cells downregulated gene sets associated with T cell activation, inflammatory response and cell migration, indicating impaired effector functions of HDAC1Off CD4+ T cells. Thus, our study demonstrates that the inhibition of the catalytic activity of HDAC1 is sufficient to achieve a clinical benefit in EAE disease development. This raises the exciting translational perspective that targeting HDAC1 enzymatic activity is a promising therapeutic strategy in treating human T cell-mediated autoimmune diseases.
2024-10-25 | GSE228259 | GEO
Project description:Vulvovaginal candidiasis (VVC) is a common mucosal infection caused by Candida spp., most frequently by Candida albicans, which may become recurrent and severely impacting the quality of life of susceptible women. Although it is increasingly being recognized that mucosal damage is mediated by an exaggerated inflammatory response, current therapeutic approaches are only based on antifungals that may relieve the symptomatology, but fail to definitely prevent recurrences. The unrestrained activation of the NLRP3 inflammasome with continuous production of IL-1? and recruitment of neutrophils is recognized as a pathogenic factor in VVC. We have previously shown that IL-22 is required to dampen pathogenic inflammasome activation in VVC via the NLRC4/IL-1Ra axis. However, IL-22 also regulates IL-18, a product of the inflammasome activity that regulates IL-22 expression. Here we describe a cross-regulatory circuit between IL-18 and IL-22 in murine VVC that is therapeutically druggable. We found that IL-18 production was dependent on IL-22 and NLRC4, and that IL-18, in turn, contributes to IL-22 activity. Like in IL-22 deficiency, IL-18 deficiency was associated with an increased susceptibility to VVC and unbalanced Th17/Treg response, suggesting that IL-18 can regulate both the innate and the adaptive responses to the fungus. Administration of the microbial metabolite indole-3-aldehyde, known to stimulate the production of IL-22 via the aryl hydrocarbon receptor (AhR), promoted IL-18 expression and protection against Candida infection. Should low levels of IL-18 be demonstrated in the vaginal fluids of women with recurrent VVC, targeting the AhR/IL-22/IL-18 pathway could be exploited for future therapeutic approaches in VVC. This study suggests that a deeper understanding of the mechanisms regulating inflammasome activity may lead to the identification of novel targets for intervention in VVC.
| S-EPMC6798081 | biostudies-literature
Project description:Dietary supplementation with fermentable fiber suppresses adiposity and the associated parameters of metabolic syndrome. Microbiota-generated fiber-derived short-chain fatty acids (SCFAs) and free fatty acid receptors including GPR43 are thought to mediate these effects. We find that while fermentable (inulin), but not insoluble (cellulose), fiber markedly protected mice against high-fat diet (HFD)-induced metabolic syndrome, the effect was not significantly impaired by either inhibiting SCFA production or genetic ablation of GPR43. Rather, HFD decimates gut microbiota, resulting in loss of enterocyte proliferation, leading to microbiota encroachment, low-grade inflammation (LGI), and metabolic syndrome. Enriching HFD with inulin restored microbiota loads, interleukin-22 (IL-22) production, enterocyte proliferation, and antimicrobial gene expression in a microbiota-dependent manner, as assessed by antibiotic and germ-free approaches. Inulin-induced IL-22 expression, which required innate lymphoid cells, prevented microbiota encroachment and protected against LGI and metabolic syndrome. Thus, fermentable fiber protects against metabolic syndrome by nourishing microbiota to restore IL-22-mediated enterocyte function.
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Project description:Background Osteoarthritis (OA) is a multifactorial disease with various risk factors, resulting in the degeneration of articular cartilage and whole joints. However, to date, no effective disease-modifying therapy for OA has been developed. Oxymatrine (OMT) is associated with many pharmacological effects, including anti-inflammatory, antiapoptotic, and antioxidative properties. However, the role of OMT in OA remains unclear. Materials and Methods An IL-1β-induced chondrocyte model and anterior cruciate ligament transection (ACLT)-induced murine model of OA were constructed. The effect of OMT on chondrocyte viability was assessed using the CCK-8 assay. The protein level was assessed by Western blot analysis, and the apoptosis rate was assessed by flow cytometry in vitro and TUNEL staining in OA model mice. The effect of OMT on the degradation of articular cartilage in ACLT-induced OA mice was assessed by histological analysis. Results OMT at 0–2 mg/mL showed no conspicuous cytotoxicity on chondrocytes after 24 hours of incubation. OMT at 0.5, 1, and 2 mg/mL inhibited IL-1β-triggered apoptosis, upregulated MMP13, MMP9, and Col X, and upregulated Col II in chondrocytes in vitro. OMT represses the NF-κB signaling cascade in IL-1β-triggered chondrocytes in vitro. In an in vivo study, OMT decreased the apoptosis rate of chondrocytes and exerted a protective effect against the degradation of articular cartilage in ACLT-triggered OA mice. Conclusion OMT plays a protective role against chondrocyte injury induced by IL-1β in vitro or ACLT in vivo. OMT may play a role in chondrocytes during OA by inhibiting NF-κB signaling by decreasing the phosphorylation of p65 and IκB. OMT treatment may be a promising chondroprotective approach to delay OA cartilage progression.
| S-EPMC9532098 | biostudies-literature
Project description:Environmental genotoxic factors pose a challenge to the genomic integrity of epithelial cells at barrier surfaces that separate host organisms from the environment. They can induce mutations that, if they occur in epithelial stem cells, contribute to malignant transformation and cancer development1-3. Genome integrity in epithelial stem cells is maintained by an evolutionarily conserved cellular response pathway, the DNA damage response (DDR). The DDR culminates in either transient cell-cycle arrest and DNA repair or elimination of damaged cells by apoptosis4,5. Here we show that the cytokine interleukin-22 (IL-22), produced by group 3 innate lymphoid cells (ILC3) and γδ T cells, is an important regulator of the DDR machinery in intestinal epithelial stem cells. Using a new mouse model that enables sporadic inactivation of the IL-22 receptor in colon epithelial stem cells, we demonstrate that IL-22 is required for effective initiation of the DDR following DNA damage. Stem cells deprived of IL-22 signals and exposed to carcinogens escaped DDR-controlled apoptosis, contained more mutations and were more likely to give rise to colon cancer. We identified metabolites of glucosinolates, a group of phytochemicals contained in cruciferous vegetables, to be a widespread source of genotoxic stress in intestinal epithelial cells. These metabolites are ligands of the aryl hydrocarbon receptor (AhR)6, and AhR-mediated signalling in ILC3 and γδ T cells controlled their production of IL-22. Mice fed with diets depleted of glucosinolates produced only very low levels of IL-22 and, consequently, the DDR in epithelial cells of mice on a glucosinolate-free diet was impaired. This work identifies a homeostatic network protecting stem cells against challenge to their genome integrity by AhR-mediated 'sensing' of genotoxic compounds from the diet. AhR signalling, in turn, ensures on-demand production of IL-22 by innate lymphocytes directly regulating components of the DDR in epithelial stem cells.
| S-EPMC6420091 | biostudies-literature