FAM64A positively regulates STAT3 activity to promote Th17 differentiation and colitis-associated carcinogenesis

STAT3 is a transcription factor that plays central roles in various physiological processes, including differentiation of Th cells. Its deregulation results in serious diseases, including inflammatory diseases and cancer. The mechanisms related to how STAT3 activity is regulated remain enigmatic. Here we show that overexpression of FAM64A potentiates IL-6–induced activation of STAT3 and expression of downstream target genes, whereas deficiency of FAM64A has the opposite effects. FAM64A interacts with STAT3 in the nucleus and regulates binding of STAT3 to the promoters of its target genes. Deficiency of Fam64a significantly impairs differentiation of Th17 but not Th1 or induced regulatory T cells (iTreg). In addition, Fam64a deficiency attenuates experimental autoimmune encephalomyelitis (EAE) and dextran sulfate sodium (DSS)-induced colitis, which is correlated with decreased differentiation of Th17 cells and production of proinflammatory cytokines. Furthermore, Fam64a deficiency suppresses azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) in mice. These findings suggest that FAM64A regulates Th17 differentiation and colitis and inflammation-associated cancer by modulating transcriptional activity of STAT3.

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VSIG4 mediates transcriptional inhibition of Nlrp3 and Il-1β in macrophages

Science Advances ◽

10.1126/sciadv.aau7426 ◽

2019 ◽

Vol 5 (1) ◽

pp. eaau7426 ◽

Cited By ~ 11

Author(s):

Xiaoyong Huang ◽

Zeqing Feng ◽

Yuanzhong Jiang ◽

Jialin Li ◽

Qun Xiang ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Nuclear Factor Κb ◽

Autoimmune Encephalomyelitis ◽

Signaling Complex ◽

Transcriptional Inhibition ◽

Surface Signaling ◽

Immunoglobulin Domain ◽

Experimental Autoimmune

Hyperactivation of the NLRP3 inflammasome contributes to the pathogenesis of multiple diseases, but the mechanisms underlying transcriptional regulation of Nlrp3 remain elusive. We demonstrate here that macrophages lacking V-set and immunoglobulin domain–containing 4 (Vsig4) exhibit significant increases in Nlrp3 and Il-1β transcription, caspase-1 activation, pyroptosis, and interleukin-1β (IL-1β) secretion in response to NLRP3 inflammasome stimuli. VSIG4 interacts with MS4A6D in the formation of a surface signaling complex. VSIG4 occupancy triggers Ser232 and Ser235 phosphorylation in MS4A6D, leading to activation of JAK2-STAT3-A20 cascades that further results in nuclear factor κB suppression and Nlrp3 and Il-1β repression. Exaggerated NLRP3 and IL-1β expression in Vsig4−/− mice is accountable for deleterious disease severity in experimental autoimmune encephalomyelitis (EAE) and resistance to dextran sulfate sodium (DSS)–induced colitis. The agonistic VSIG4 antibodies (VG11), acting through NLRP3 and IL-1β suppression, show significant therapeutic efficacy in mouse EAE. These findings highlight VSIG4 as a prospective target for treating NLRP3-associated inflammatory disorders.

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Pivotal Roles of T-Helper 17-Related Cytokines, IL-17, IL-22, and IL-23, in Inflammatory Diseases

Clinical and Developmental Immunology ◽

10.1155/2013/968549 ◽

2013 ◽

Vol 2013 ◽

pp. 1-13 ◽

Cited By ~ 75

Author(s):

Ning Qu ◽

Mingli Xu ◽

Izuru Mizoguchi ◽

Jun-ichi Furusawa ◽

Kotaro Kaneko ◽

...

Keyword(s):

Th17 Cell ◽

Th17 Cells ◽

Functional Role ◽

Inflammatory Diseases ◽

Interleukin 17 ◽

T Helper ◽

T Helper 17 ◽

Autoimmune Encephalomyelitis ◽

Experimental Autoimmune

T-helper 17 (Th17) cells are characterized by producing interleukin-17 (IL-17, also called IL-17A), IL-17F, IL-21, and IL-22 and potentially TNF-α and IL-6 upon certain stimulation. IL-23, which promotes Th17 cell development, as well as IL-17 and IL-22 produced by the Th17 cells plays essential roles in various inflammatory diseases, such as experimental autoimmune encephalomyelitis, rheumatoid arthritis, colitis, and Concanavalin A-induced hepatitis. In this review, we summarize the characteristics of the functional role of Th17 cells, with particular focus on the Th17 cell-related cytokines such as IL-17, IL-22, and IL-23, in mouse models and human inflammatory diseases.

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Aspirin metabolite sodium salicylate selectively inhibits transcriptional activity of ATF6α and downstream target genes

Scientific Reports ◽

10.1038/s41598-017-09500-x ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 2

Author(s):

Fernanda L. B. Mügge ◽

Aristóbolo M. Silva

Keyword(s):

Transcriptional Activity ◽

Target Genes ◽

Sodium Salicylate ◽

Downstream Target

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4-Ethylguaiacol modulates neuroinflammation and Th1/Th17 differentiation to ameliorate disease severity in experimental autoimmune encephalomyelitis

Journal of Neuroinflammation ◽

10.1186/s12974-021-02143-w ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Wen-Tsan Weng ◽

Ping-Chang Kuo ◽

Dennis A. Brown ◽

Barbara A. Scofield ◽

Destin Furnas ◽

...

Keyword(s):

Autoimmune Disease ◽

Experimental Autoimmune Encephalomyelitis ◽

Immune Responses ◽

Disease Progression ◽

Disease Severity ◽

Autoimmune Encephalomyelitis ◽

Relapsing Remitting ◽

Th17 Differentiation ◽

Experimental Autoimmune

Abstract Background Multiple sclerosis (MS) is a progressive autoimmune disease characterized by the accumulation of pathogenic inflammatory immune cells in the central nervous system (CNS) that subsequently causes focal inflammation, demyelination, axonal injury, and neuronal damage. Experimental autoimmune encephalomyelitis (EAE) is a well-established murine model that mimics the key features of MS. Presently, the dietary consumption of foods rich in phenols has been reported to offer numerous health benefits, including anti-inflammatory activity. One such compound, 4-ethylguaiacol (4-EG), found in various foods, is known to attenuate inflammatory immune responses. However, whether 4-EG exerts anti-inflammatory effects on modulating the CNS inflammatory immune responses remains unknown. Thus, in this study, we assessed the therapeutic effect of 4-EG in EAE using both chronic and relapsing-remitting animal models and investigated the immunomodulatory effects of 4-EG on neuroinflammation and Th1/Th17 differentiation in EAE. Methods Chronic C57BL/6 EAE and relapsing-remitting SJL/J EAE were induced followed by 4-EG treatment. The effects of 4-EG on disease progression, peripheral Th1/Th17 differentiation, CNS Th1/Th17 infiltration, microglia (MG) activation, and blood-brain barrier (BBB) disruption in EAE were evaluated. In addition, the expression of MMP9, MMP3, HO-1, and Nrf2 was assessed in the CNS of C57BL/6 EAE mice. Results Our results showed that 4-EG not only ameliorated disease severity in C57BL/6 chronic EAE but also mitigated disease progression in SJL/J relapsing-remitting EAE. Further investigations of the cellular and molecular mechanisms revealed that 4-EG suppressed MG activation, mitigated BBB disruption, repressed MMP3/MMP9 production, and inhibited Th1 and Th17 infiltration in the CNS of EAE. Furthermore, 4-EG suppressed Th1 and Th17 differentiation in the periphery of EAE and in vitro Th1 and Th17 cultures. Finally, we found 4-EG induced HO-1 expression in the CNS of EAE in vivo as well as in MG, BV2 cells, and macrophages in vitro. Conclusions Our work demonstrates that 4-EG confers protection against autoimmune disease EAE through modulating neuroinflammation and inhibiting Th1 and Th17 differentiation, suggesting 4-EG, a natural compound, could be potentially developed as a therapeutic agent for the treatment of MS/EAE.

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IFN-β regulates Th17 differentiation partly through the inhibition of osteopontin in experimental autoimmune encephalomyelitis

Molecular Immunology ◽

10.1016/j.molimm.2017.11.002 ◽

2018 ◽

Vol 93 ◽

pp. 20-30 ◽

Cited By ~ 5

Author(s):

Qing Zhao ◽

Wenjing Cheng ◽

Yebin Xi ◽

Zheyi Cao ◽

Yunzhi Xu ◽

...

Keyword(s):

Experimental Autoimmune Encephalomyelitis ◽

Autoimmune Encephalomyelitis ◽

Th17 Differentiation ◽

Experimental Autoimmune

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Genetic evidence for the transcriptional-activating function of Homothorax during adult fly development

Development ◽

10.1242/dev.128.18.3405 ◽

2001 ◽

Vol 128 (18) ◽

pp. 3405-3413 ◽

Cited By ~ 4

Author(s):

Adi Inbal ◽

Naomi Halachmi ◽

Charna Dibner ◽

Dale Frank ◽

Adi Salzberg

Keyword(s):

Transcriptional Activity ◽

Target Genes ◽

Genetic Evidence ◽

In Vivo Studies ◽

Loss Of Function ◽

Native Form ◽

Downstream Target ◽

Activating Function

Homothorax (HTH) is a homeobox-containing protein, which plays multiple roles in the development of the embryo and the adult fly. HTH binds to the homeotic cofactor Extradenticle (EXD) and translocates it to the nucleus. Its function within the nucleus is less clear. It was shown, mainly by in vitro studies, that HTH can bind DNA as a part of ternary HTH/EXD/HOX complexes, but little is known about the transcription regulating function of HTH-containing complexes in the context of the developing fly. Here we present genetic evidence, from in vivo studies, for the transcriptional-activating function of HTH. The HTH protein was forced to act as a transcriptional repressor by fusing it to the Engrailed (EN) repression domain, or as a transcriptional activator, by fusing it to the VP16 activation domain, without perturbing its ability to translocate EXD to the nucleus. Expression of the repressing form of HTH in otherwise wild-type imaginal discs phenocopied hth loss of function. Thus, the repressing form was working as an antimorph, suggesting that normally HTH is required to activate the transcription of downstream target genes. This conclusion was further supported by the observation that the activating form of HTH caused typical hth gain-of-function phenotypes and could rescue hth loss-of-function phenotypes. Similar results were obtained with XMeis3, the Xenopus homologue of HTH, extending the known functional similarity between the two proteins. Competition experiments demonstrated that the repressing forms of HTH or XMeis3 worked as true antimorphs competing with the transcriptional activity of the native form of HTH. We also describe the phenotypic consequences of HTH antimorph activity in derivatives of the wing, labial and genital discs. Some of the described phenotypes, for example, a proboscis-to-leg transformation, were not previously associated with alterations in HTH activity. Observing the ability of HTH antimorphs to interfere with different developmental pathways may direct us to new targets of HTH. The HTH antimorph described in this work presents a new means by which the transcriptional activity of the endogenous HTH protein can be blocked in an inducible fashion in any desired cells or tissues without interfering with nuclear localization of EXD.

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TLR4-RelA-miR-30a signal pathway regulates Th17 differentiation during experimental autoimmune encephalomyelitis development

Journal of Neuroinflammation ◽

10.1186/s12974-019-1579-0 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 3

Author(s):

Xuebin Qu ◽

Jingjing Han ◽

Ying Zhang ◽

Xingqi Wang ◽

Hongbin Fan ◽

...

Keyword(s):

T Cells ◽

Experimental Autoimmune Encephalomyelitis ◽

Th17 Cells ◽

Signal Pathway ◽

Autoimmune Encephalomyelitis ◽

Naive T Cells ◽

Naïve T Cells ◽

Th17 Differentiation ◽

Experimental Autoimmune

Abstract Background Toll-like receptor 4 (TLR4) is well known for activating the innate immune system; however, it is also highly expressed in adaptive immune cells, such as CD4+ T-helper 17 (Th17) cells, which play a key role in multiple sclerosis (MS) pathology. However, the function and governing mechanism of TLR4 in Th17 remain unclear. Methods The changes of TLR4 in CD4+ T cells from MS patients and experimental autoimmune encephalomyelitis (EAE) mice were tested. TLR4-deficient (TLR4−/−) naïve T cells were induced in vitro and transferred into Rag1−/− mice to measure Th17 differentiation and EAE pathology. DNA sequence analyses combining with deletion fragments and mutation analyses, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA) were used to explore the mechanism of TLR4 signaling pathway in regulating Th17 differentiation. Results The levels of TLR4 were increased in CD4+ Th17 cells both from MS patients and EAE mice, as well as during Th17 differentiation in vitro. TLR4−/− CD4+ naïve T cells inhibited their differentiation into Th17, and transfer of TLR4−/− CD4+ naïve T cells into Rag1−/− mice was defective in promoting EAE, characterized by less demyelination and Th17 infiltration in the spinal cord. TLR4 signal enhanced Th17 differentiation by activating RelA, downregulating the expression of miR-30a, a negative regulator of Th17 differentiation. Inhibition of RelA activity increased miR-30a level, but decreased Th17 differentiation rate. Furthermore, RelA directly regulated the expression of miR-30a via specific binding to a conserved element of miR-30a gene. Conclusions TLR4−/− CD4+ naïve T cells are inadequate in differentiating to Th17 cells both in vitro and in vivo. TLR4-RelA-miR-30a signal pathway regulates Th17 differentiation via direct binding of RelA to the regulatory element of miR-30a gene. Our results indicate modulating TLR4-RelA-miR-30a signal in Th17 may be a therapeutic target for Th17-mediated neurodegeneration in neuroinflammatory diseases.

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