scholarly journals Aging weakens Th17 cell pathogenicity and ameliorates experimental autoimmune uveitis in mice

2021 ◽  
Author(s):  
He Li ◽  
Lei Zhu ◽  
Rong Wang ◽  
Lihui Xie ◽  
Jie Ren ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Th17 Cells ◽  
Immune Cell ◽  
Experimental Autoimmune Uveitis ◽  
T Helper 17 ◽  
Autoimmune Uveitis ◽  
Gm Csf ◽  
The Impact ◽  
Old Mice ◽  
Experimental Autoimmune

AbstractAging-induced changes in the immune system are associated with a higher incidence of infection and vaccination failure. Lymph nodes, which filter the lymph to identify and fight infections, play a central role in this process. However, careful characterization of the impact of aging on lymph nodes and associated autoimmune diseases is lacking. We combined single-cell RNA sequencing (scRNA-seq) with flow cytometry to delineate the immune cell atlas of cervical draining lymph nodes (CDLNs) of both young and old mice with or without experimental autoimmune uveitis (EAU). We found extensive and complicated changes in the cellular constituents of CDLNs during aging. When confronted with autoimmune challenges, old mice developed milder EAU compared to young mice. Within this EAU process, we highlighted that the pathogenicity of T helper 17 cells (Th17) was dampened, as shown by reduced GM-CSF secretion in old mice. The mitigated secretion of GM-CSF contributed to alleviation of IL-23 secretion by antigen-presenting cells (APCs) and may, in turn, weaken APCs’ effects on facilitating the pathogenicity of Th17 cells. Meanwhile, our study further unveiled that aging downregulated GM-CSF secretion through reducing both the transcript and protein levels of IL-23R in Th17 cells from CDLNs. Overall, aging altered immune cell responses, especially through toning down Th17 cells, counteracting EAU challenge in old mice.

scholarly journals Deficiency of IL-27 Signaling Exacerbates Experimental Autoimmune Uveitis with Elevated Uveitogenic Th1 and Th17 Responses

2021 ◽  
Vol 22 (14) ◽  
pp. 7517
Author(s):  
Sihan Wu ◽  
Rui Ma ◽  
Yajie Zhong ◽  
Zilin Chen ◽  
Hongyan Zhou ◽  
...  
Keyword(s):  
Th17 Cells ◽  
Therapeutic Potential ◽  
Ocular Inflammation ◽  
Experimental Autoimmune Uveitis ◽  
Autoimmune Uveitis ◽  
Gm Csf ◽  
Macrophage Colony ◽  
Cd4 Cell ◽  
Tr1 Cells ◽  
Experimental Autoimmune

Human uveitis is an autoimmune disease of the central nervous system that is characterized by ocular inflammation with the involvement of uveitogenic Th1 and Th17 responses. In experimental autoimmune uveitis (EAU), the animal model for human uveitis, both responses are proven to be critical in disease development. Therefore, targeting both Th1 and Th17 cells has therapeutic implication for disease resolution. IL-27 is a multifunctional cytokine that can either promote or inhibit T cell responses and is implicated in both autoimmune and infectious diseases. The aim of this study is to characterize the role of IL-27/IL-27R signaling in regulating uveitogenic Th1/Th17 responses in EAU. By immunizing IL-27Rα−/− mice and their wild-type (WT) littermates for EAU, we demonstrated that IL-27 signaling deficiency exacerbated EAU with severe ocular inflammation and impairment of visual function. Furthermore, there was a significant increase in the eye-infiltrating Th1 and Th17 cells in IL-27Rα−/− EAU mice compared to WT. Their retinal antigen-specific Th1 and Th17 responses were also significantly increased, as represented by the elevation of their signature cytokines, IFN-γ and IL-17A, respectively. We also observed the upregulation of another pathogenic cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), from effector T cells in IL-27Rα−/− EAU mice. Mechanistic studies confirmed that IL-27 inhibited GM-CSF production from Th17 cells. In addition, the induction of IL-10 producing type 1 regulatory T (Tr1) cells was impaired in IL-27Rα−/− EAU mice. These results identified that IL-27 signaling plays a suppressive role in EAU by regulating multiple CD4+ cell subsets, including the effector Th1 and Th17 cells and the regulatory Tr1 cells. Our findings provide new insights for therapeutic potential in controlling uveitis by enhancing IL-27 signaling.

scholarly journals KS23, a novel peptide derived from adiponectin, inhibits retinal inflammation and downregulates the proportions of Th1 and Th17 cells during experimental autoimmune uveitis

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Tian Niu ◽  
Lu Cheng ◽  
Hanying Wang ◽  
Shaopin Zhu ◽  
Xiaolu Yang ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Intraperitoneal Injection ◽  
Chemokine Receptors ◽  
Th17 Cells ◽  
Experimental Autoimmune Uveitis ◽  
Safe Alternative ◽  
Autoimmune Uveitis ◽  
Expression Levels ◽  
Anti Inflammatory ◽  
Experimental Autoimmune

Abstract Background Uveitis is a potentially sight-threatening form of ocular inflammation that affects the uvea in the wall of the eye. Currently available treatments for uveitis have exhibited profound adverse side effects. However, KS23 is a novel 23-amino-acid anti-inflammatory peptide derived from adiponectin that may have the capability to function as a safe alternative to these existing treatment options. We, therefore, evaluated the preventive effect of KS23 in experimental autoimmune uveitis (EAU). Methods EAU was induced in mice via immunization with the peptide interphotoreceptor retinoid binding protein 161–180 (IRBP161–180). KS23 was then administered every 2 days via intraperitoneal injection to induce protection against EAU. Clinical and histopathological scores were employed to evaluate the disease progression. Inflammatory cytokines were also quantified using ELISA, and the expression levels of specific chemokines and chemokine receptors were assessed via qRT-PCR. In addition, the proportions of Th1 and Th17 cells were detected via flow cytometry, and the expression levels of specific proteins were quantified from the retina of mice using western blot analysis, to elucidate the specific mechanism of action employed by KS23 to suppress the inflammation associated with EAU. Results KS23 was found to significantly improve EAU-associated histopathological scores, while decreasing the expression of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-6, and IL-17A), chemokines (LARC, RANTES, MIG, IP-10), and chemokine receptors (CCR6 and CXCR3). The proportions of Th1 and Th17 cells were also suppressed following intraperitoneal injection with KS23. The anti-inflammatory mechanism employed by KS23 was determined to be associated with the activation of AMPK and subsequent inhibition of NF-κB. Conclusions KS23 decreased the proportions of Th1 and Th17 cells to effectively ameliorate the progression of EAU. It may, therefore, serve as a promising potential therapeutic agent for uveitis.

scholarly journals Intraperitoneal Infusion of Mesenchymal Stem/Stromal Cells Prevents Experimental Autoimmune Uveitis in Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Joo Youn Oh ◽  
Tae Wan Kim ◽  
Hyun Jeong Jeong ◽  
Hyun Ju Lee ◽  
Jin Suk Ryu ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Th17 Cells ◽  
Time Course ◽  
Intraperitoneal Administration ◽  
Experimental Autoimmune Uveitis ◽  
Autoimmune Uveitis ◽  
Th17 Differentiation ◽  
Retinal Structure ◽  
Time Course Study ◽  
Experimental Autoimmune

Autoimmune uveitis is one of the leading causes of blindness. We here investigated whether intraperitoneal administration of human mesenchymal stem/stromal cells (hMSCs) might prevent development of experimental autoimmune uveitis (EAU) in mice. Time course study showed that the number of IFN-γ- or IL-17-expressing CD4+T cells was increased in draining lymph nodes (DLNs) on the postimmunization day 7 and decreased thereafter. The retinal structure was severely disrupted on day 21. An intraperitoneal injection of hMSCs at the time of immunization protected the retina from damage and suppressed the levels of proinflammatory cytokines in the eye. Analysis of DLNs on day 7 showed that hMSCs decreased the number of Th1 and Th17 cells. The hMSCs did not reduce the levels of IL-1β, IL-6, IL-12, and IL-23 which are the cytokines that drive Th1/Th17 differentiation. Also, hMSCs did not induce CD4+CD25+Foxp3+cells. However, hMSCs increased the level of an immunoregulatory cytokine IL-10 and the population of IL-10-expressing B220+CD19+cells. Together, data demonstrate that hMSCs attenuate EAU by suppressing Th1/Th17 cells and induce IL-10-expressing B220+CD19+cells. Our results support suggestions that hMSCs may offer a therapy for autoimmune diseases mediated by Th1/Th17 responses.

Persistence of IL-2 expressing Th17 cells in healthy humans and experimental autoimmune uveitis

2011 ◽  
Vol 41 (12) ◽  
pp. 3495-3505 ◽  
Author(s):  
Cheng-Rong Yu ◽  
Hyun-Mee Oh ◽  
Nady Golestaneh ◽  
Ahjoku Amadi-Obi ◽  
Yun S. Lee ◽  
...  
Keyword(s):  
Th17 Cells ◽  
Experimental Autoimmune Uveitis ◽  
Autoimmune Uveitis ◽  
Healthy Humans ◽  
Experimental Autoimmune

scholarly journals Severity of Experimental Autoimmune Uveitis Is Reduced by Pretreatment with Live Probiotic Escherichia coli Nissle 1917

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 23
Author(s):  
Otakar Dusek ◽  
Alena Fajstova ◽  
Aneta Klimova ◽  
Petra Svozilkova ◽  
Tomas Hrncir ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Lymph Nodes ◽  
Developed Countries ◽  
T Cell Response ◽  
Experimental Autoimmune Uveitis ◽  
Cervical Lymph Nodes ◽  
Autoimmune Uveitis ◽  
Escherichia Coli Nissle 1917 ◽  
Escherichia Coli Nissle ◽  
Experimental Autoimmune

Non-infectious uveitis is considered an autoimmune disease responsible for a significant burden of blindness in developed countries and recent studies have linked its pathogenesis to dysregulation of the gut microbiota. We tested the immunomodulatory properties of two probiotics, Escherichia coli Nissle 1917 (EcN) and E. coli O83:K24:H31 (EcO), in a model of experimental autoimmune uveitis (EAU). To determine the importance of bacterial viability and treatment timing, mice were orally treated with live or autoclaved bacteria in both preventive and therapeutic schedules. Disease severity was assessed by ophthalmoscopy and histology, immune phenotypes in mesenteric and cervical lymph nodes were analyzed by flow cytometry and the gut immune environment was analyzed by RT-PCR and/or gut tissue culture. EcN, but not EcO, protected against EAU but only as a live organism and only when administered before or at the time of disease induction. Successful prevention of EAU was accompanied by a decrease in IRBP-specific T cell response in the lymph nodes draining the site of immunization as early as 7 days after the immunization and eye-draining cervical lymph nodes when the eye inflammation became apparent. Furthermore, EcN promoted an anti-inflammatory response in Peyer’s patches, increased gut antimicrobial peptide expression and decreased production of inducible nitric oxide synthase in macrophages. In summary, we show here that EcN controls inflammation in EAU and suggest that probiotics may have a role in regulating the gut–eye axis.

Interferon-β is a key regulator of proinflammatory events in experimental autoimmune encephalomyelitis

2010 ◽  
Vol 16 (12) ◽  
pp. 1458-1473 ◽  
Author(s):  
CL Galligan ◽  
LM Pennell ◽  
TT Murooka ◽  
E Baig ◽  
B Majchrzak-Kita ◽  
...  
Keyword(s):  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Lymph Nodes ◽  
Th17 Cells ◽  
Cell Activation ◽  
Immune Cell ◽  
Disease Onset ◽  
Rapid Progression ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Background: Interferon (IFN)-β is an effective therapy for relapsing-remitting multiple sclerosis, yet its mechanism of action remains ill-defined. Objectives: Our objective was to characterize the role of IFN-β in immune regulation in experimental autoimmune encephalomyelitis (EAE). Methods: IFN-β +/+ and IFN-β—/— mice were immunized with myelin oligodendrocyte glycoprotein peptide in the presence or absence of IFN-β, to induce EAE. Disease pathogenesis was monitored in the context of incidence, time of onset, clinical score, and immune cell activation in the brains, spleens and lymph nodes of affected mice. Results: Compared with IFN-β+/+ mice, IFN-β—/ — mice exhibited an earlier onset and a more rapid progression of EAE, increased numbers of CD11b+ leukocytes infiltrating affected brains and an increased percentage of Th17 cells in the central nervous system and draining lymph nodes. IFN-β treatment delayed disease onset and reduced disease severity. Ex vivo experiments revealed that the lack of IFN-β results in enhanced generation of autoreactive T cells, a likely consequence of the absence of IFN-β-regulated events in both the CD4+ T cells and antigen-presenting dendritic cells. Gene expression analysis of IFN-β-treated bone marrow macrophages (CD11b +) identified modulation of genes affecting T cell proliferation and Th17 differentiation. Conclusions: We conclude that IFN-β acts to suppress the generation of autoimmune-inducing Th17 cells during the development of disease as well as modulating pro-inflammatory mediators.

scholarly journals CD47 Deficiency Ameliorates Ocular Autoimmune Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Yoko Okunuki ◽  
Steven J. Tabor ◽  
May Y. Lee ◽  
Kip M. Connor
Keyword(s):  
Immune Cell ◽  
Transmembrane Protein ◽  
Regulatory Protein ◽  
Multiple Roles ◽  
Experimental Autoimmune Uveitis ◽  
Cellular Functions ◽  
Autoimmune Uveitis ◽  
Autoimmune Inflammation ◽  
Disease Induction ◽  
Experimental Autoimmune

Autoimmune uveitis is a sight-threatening ocular inflammatory condition in which the retina and uveal tissues become a target of autoreactive immune cells. The CD47 is a ubiquitously expressed transmembrane protein which plays multiple roles in fundamental cellular functions including phagocytosis, proliferation, and adhesion. Signal regulatory protein alpha (SIRPα), one of the CD47 ligands, is predominantly expressed in myeloid lineage cells such as dendritic cells (DCs) or macrophages, and CD47-SIRPα signaling pathway is implicated in the development of autoimmune diseases. Our current study demonstrates how CD47 depletion is effective in the prevention of experimental autoimmune uveitis (EAU), an animal model of human autoimmune uveitis, in animals deficient of CD47 (CD47-/-). Systemic suppression of SIRPα+ DCs in animals deficient in CD47 resulted in the inability of autoreactive CD4+ T cells to develop, which is crucial to induction of EAU. Of interest, retinal microglia, the resident immune cell of the retina, express SIRPα, however these cells were not operative in EAU suppression in response to CD47 depletion. These results identify CD47 as a significant regulator in the development of SIRPα+ DCs that is vital to disease induction in EAU.

Imbalance Between Th17 Cells and Regulatory T Cells During Monophasic Experimental Autoimmune Uveitis

Inflammation ◽  
2015 ◽  
Vol 39 (1) ◽  
pp. 113-122 ◽  
Author(s):  
Lian Zhang ◽  
Fangzhu Wan ◽  
Jike Song ◽  
Kai Tang ◽  
Fengming Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Th17 Cells ◽  
Experimental Autoimmune Uveitis ◽  
Autoimmune Uveitis ◽  
Experimental Autoimmune
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