IL-6-mediated Th17 differentiation through RORγt is essential for the initiation of experimental autoimmune myocarditis

Yamashita, Tomomi; Iwakura, Tomohiko; Matsui, Kazuki; Kawaguchi, Haruyo; Obana, Masanori; Hayama, Akiko; Maeda, Makiko; Izumi, Yasukatsu; Komuro, Issei; Ohsugi, Yoshiyuki; Fujimoto, Minoru; Naka, Tetsuji; Kishimoto, Tadamitsu; Nakayama, Hiroyuki; Fujio, Yasushi

doi:10.1093/cvr/cvr148

Cited by 75 publications

(64 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IL-17, a potent inflammatory cytokine, induces the expression of numerous proinflammatory cytokines, chemokines, and metalloproteinases, and plays a major role in neutrophil proliferation, survival, and chemotaxis [35,36]. Furthermore, some reports indicate that Th17 cells contribute to the pathogenesis of EAM [28,29,[37][38][39]. According to the above investigation, HMGB1 blockade attenuates cardiac pathological changes and reduces the number of infiltrating inflammatory cells (Fig.…”

Section: Discussionmentioning

confidence: 79%

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

Sun

Zhou

et al. 2011

Eur J Immunol

View full text Add to dashboard Cite

High-mobility group box 1 (HMGB1), a non-histone nuclear protein, has been implicated in cardiovascular diseases. Dilated cardiomyopathy (DCM), one of the leading causes of heart failure, is often caused by coxsackievirus B3-triggered myocarditis and promoted by the post-infectious autoimmune process. Th17 cells, a novel CD4 1 T subset, may be important in the pathogenesis of autoimmune myocarditis. In the present study, we attempted to block HMGB1 function with a monoclonal antibody specific for HMGB1 B box and investigated the effects of the blockade on Th17 cells and experimental autoimmune myocarditis (EAM). After induction of EAM, HMGB1 protein levels were significantly elevated both in the heart and blood. Administration of an anti-HMGB1 B box mAb attenuated cardiac pathological changes and reduced the number of infiltrating inflammatory cells in the heart during EAM. These protective effects of HMGB1 blockade correlated with a reduced number of Th17 cells in local tissues and lower levels of IL-17 in the serum. Furthermore, in vitro, studies demonstrated that HMGB1 promoted Th17-cell expansion. Therefore, we speculate that HMGB1 blockade ameliorates cardiac pathological changes in EAM by suppressing Th17 cells.Key words: Dilated cardiomyopathy . Experimental myocarditis . HMGB1 . Th17 cells IntroductionHigh-mobility group box 1 (HMGB1), a non-histone nuclear protein, has been functionally characterized as an alarmin or damage-associated molecular pattern (DAMP) [1,2]. It is constitutively expressed in quiescent cells and stored in the nucleus [3]. HMGB1 is one of the most evolutionarily conserved proteins in eukaryotes, with 100% identity between mice and rats, and 99% identity between rodents and humans [3].HMGB1 has been shown to be involved in both infectious and non-infectious inflammatory disease [2,4]. HMGB1 is released into the extracellular milieu during cell apoptosis/death [5], and by macrophages and monocytes in response to cellular stress or injury [6]. HMGB1 binds to the endogenous receptor for advanced glycation endproducts [7], exogenous toll-like receptor 2/4/9 (TLR2/4/9) [8,9], and CD24/Siglec-10 [10], and induces the expression of proinammatory cytokines, chemokines, and adhesion molecules [3,6]. Although, HMGB1 was initially 3586thought to be a late mediator of sepsis, recent data also indicated that HMGB1 is associated with many other pathological conditions, such as autoimmune disease [11], cancer [12][13][14], trauma, ischemia-reperfusion injury [15,16], tissue repair and regeneration [17,18], and cardiovascular diseases [19]. Furthermore, HMGB1 has restorative effects on CD4 1 T-helper cell modulation [20].Dilated cardiomyopathy (DCM) is one of the leading causes of severe heart failure and the most common indication for heart transplantation. DCM is often caused by coxsackievirus B3-triggered myocarditis [21]. Experimental autoimmune myocarditis (EAM) is a mouse model of postinfectious myocarditis, characterized by inflammatory infiltration of the myocardium and cardiac myocyte ne...

show abstract

Section: Discussionmentioning

confidence: 79%

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

Sun

Zhou

et al. 2011

Eur J Immunol

View full text Add to dashboard Cite

show abstract

“…The recently identified Th17 subset 142 has been implicated in the onset of chronic myocarditis. 143 These cells secrete high levels of IL-17 and have been implicated in autoantibody production. 142,144 Research conducted on the Th17 subset in the context of CVB3 myocarditis suggests that these cells may contribute to chronic myocarditis through persistent inflammatory signals provided by secretion of IL-17.…”

Section: T-helper 17 Cells Play a Role In Chronic Inflammationmentioning

confidence: 99%

“…Enhanced IL-17 and Th17 specific transcription factor, ROR␥t, were also increased consistent with expansion of this cell type. 143 Interleukin-17 and its various isotypes can induce expression of TNF-␣ and Th2 responses, which in turn induce a prolonged inflammatory environment that might foster the production of auto-antibodies. Though autoimmune mechanisms of damage to the heart during chronic myocarditis may seem to be exclusive of the initial infectious insult, there is reason to believe that virus infection and inflammation are more interdependent than previously thought.…”

Section: T-helper 17 Cells Play a Role In Chronic Inflammationmentioning

confidence: 99%

Inflammation in Myocardial Diseases

Marchant

Boyd

Lin

et al. 2012

Circulation Research

252

165

View full text Add to dashboard Cite

Inflammatory processes underlie a broad spectrum of conditions that injure the heart muscle and cause both structural and functional deficits. In this article, we address current knowledge regarding 4 common forms of myocardial inflammation: myocardial ischemia and reperfusion, sepsis, viral myocarditis, and immune rejection. Each of these pathological states has its own unique features in pathogenesis and disease evolution, but all reflect inflammatory mechanisms that are partially shared. From the point of injury to the mobilization of innate and adaptive immune responses and inflammatory amplification, the cellular and soluble mediators and mechanisms examined in this review will be discussed with a view that both beneficial and adverse consequences arise in these human conditions. (Circ Res. 2012;110:126-144.)

show abstract

“…For Th17 cells, substantial evidence had demonstrated that they are involved in the pathogenesis of inflammatory diseases. It had been found that anti-IL-6 treatment could reduce the proportion of Th17 cells, reducing the inflammatory reaction of autoimmune myocarditis [19]. In viral myocarditis, Yang et al found that administration of recombinant IL-23 reduced the percentage of Th17 cells and inflammation in mice [20].…”

Section: Discussionmentioning

confidence: 99%

The cholinergic anti-inflammatory pathway ameliorates acute viral myocarditis in mice by regulating CD4⁺ T cell differentiation

et al. 2018

View full text Add to dashboard Cite

Many studies have found that abnormalities in the proportion and differentiation of CD4+ T cells (Th cells) are closely related to the pathogenesis of viral myocarditis (VMC). Our previous research indicates that the cholinergic anti-inflammatory pathway (CAP) attenuates the inflammatory response of VMC and downregulates the expression of cytokines in Th1 and Th17 cells. This suggests that the cholinergic anti-inflammatory pathway likely attenuates the inflammatory response in VMC by altering Th cell differentiation. The aim of this study is to investigate the effect of CAP on CD4+ T cell differentiation in VMC mice. CD4+ T cells in the spleen of VMC mice were obtained and cultured in the presence of nicotine or methyllycaconitine (MLA). Cells were harvested and analyzed for the percentage of each Th cell subset by flow cytometry and transcription factor release by Western blot. Then, we detected the effect of CAP on the differentiation of Th cells in vivo. Nicotine or MLA was used to activate and block CAP, respectively, in acute virus-induced myocarditis. Nicotine treatment increased the proportion of Th2 and Treg cells, decreased the proportion of Th1 and Th17 cells in the spleen, reduced the level of proinflammatory cytokines, and attenuated the severity of myocardium lesions and cellular infiltration in viral myocarditis. MLA administration had the opposite effect. Our result demonstrated that CAP effectively protects the myocardium from virus infection, which may be attributable to the regulation of Th cell differentiation.

show abstract

IL-6-mediated Th17 differentiation through RORγt is essential for the initiation of experimental autoimmune myocarditis

Abstract: IL-6-mediated induction of Th17 cells is critical for the onset of EAM, but not for its progression. IL-6/Th17 signalling could be a promising therapeutic target for the prevention of myocardial inflammation.

Cited by 75 publications

References 23 publications

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

Inflammation in Myocardial Diseases

The cholinergic anti-inflammatory pathway ameliorates acute viral myocarditis in mice by regulating CD4⁺ T cell differentiation

Contact Info

Product

Resources

About

IL-6-mediated Th17 differentiation through RORγt is essential for the initiation of experimental autoimmune myocarditis

Abstract: IL-6-mediated induction of Th17 cells is critical for the onset of EAM, but not for its progression. IL-6/Th17 signalling could be a promising therapeutic target for the prevention of myocardial inflammation.

Cited by 75 publications

References 23 publications

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

Inflammation in Myocardial Diseases

The cholinergic anti-inflammatory pathway ameliorates acute viral myocarditis in mice by regulating CD4+ T cell differentiation

Contact Info

Product

Resources

About

The cholinergic anti-inflammatory pathway ameliorates acute viral myocarditis in mice by regulating CD4⁺ T cell differentiation