Exercise activates the hypothalamic S1PR1–STAT3 axis through the central action of interleukin 6 in mice

Silva, Vagner R. R.; Micheletti, Thayana O.; Katashima, Carlos K.; Lenhare, Luciene; Morari, Joseane; Moura‐Assis, Alexandre; Lima-Júnior, José Carlos de; Camargo, Juliana Alves de; Passos, Gabriela Reolon; Gaspar, Rodrigo S.; Velloso, Lı́cio A.; Saad, Mário José Abdalla; Silva, Adelino Sánchez Ramos da; Moura, Leandro Pereira de; Cintra, Dennys Esper; Pauli, José Rodrigo; Ropelle, Eduardo Rochete

doi:10.1002/jcp.26818

Cited by 11 publications

(13 citation statements)

References 37 publications

(79 reference statements)

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“…The present study demonstrated that the RHD group also exhibited a decreased S1PR1 expression and an increased STAT3 phosphorylation compared with that in the control group. However, an increase in S1PR1 expression has been reported to increase the phosphorylation of STAT3 ( 23 , 39 ); however, these studies did not examine RHD. Combined with the uncertainty of the expression of S1PR1 in the different heart diseases mentioned above, it can be concluded that the expression of S1PR1 and its role in regulating the phosphorylation of STAT3 in different diseases and different physiological or pathological processes may not be static.…”

Section: Discussionmentioning

confidence: 97%

Interference with the expression of S1PR1 or STAT3 attenuates valvular damage due to rheumatic heart disease

Xian

Chen

et al. 2021

Int J Mol Med

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Rheumatic heart disease (RHd) affects numerous individuals annually; however, its pathogenesis remains unclear. The sphingosine 1-phosphate receptor 1 (S1PR1) and signal transducer and activator of transcription 3 (STAT3) have recently been shown to be involved in valvular damage via the promotion of the differentiation of T helper 17 (Th17) cells during the development of RHd-induced valvular damage. The present study investigated whether altering the expression of S1PR1 or STAT3 attenuates valvular damage due to RHd. Inactivated group A streptococcus (GAS) was used to establish a rat model of RHd. Recombinant adeno-associated viral vectors carrying an S1PR1 overexpression sequence were used to overexpress S1PR1. STAT3 small interfering RNA (STAT3-siRNA) was used to inhibit STAT3 expression. Reverse transcription-quantitative PcR (RT-qPcR) was performed to detect the mRNA expression of S1PR1, STAT3, collagen type III α1 chain (Col3a1) and fibroblast-specific protein 1. Western blotting (WB) and immunohistochemistry were used to detect the levels of S1PR1, STAT3, phosphorylated (p-) STAT3, and retinoic acid-related orphan receptor γT (RORγt) proteins. Enzyme-linked immunosorbent assays (ELISAs) and immunohistochemistry were used to detect the levels of interleukin (IL)-6 and IL-17. Hematoxylin and eosin (H&E) staining and Sirius Red staining were performed to evaluate the degree of inflammation and fibrosis in the valvular tissues. S1PR1 expression was decreased in the valvular tissues of the rats with RHd. The levels of IL-6, IL-17 and p-STAT3 in the rats with RHD were increased. The degree of valvular inflammation and fibrosis in the rats with RHD was also increased. The overexpression of S1PR1 and the inhibition of STAT3 reduced the total p-STAT3 level, resulting in decreased levels of IL-6, IL-17 and RORγt, and a reduced degree of valvular inflammation and fibrosis. These results suggest that the expression of S1PR1 and STAT3 may be involved in valvular tissue damage due to RHd. Thus, strategies designed to interfere with the expression of S1PR1 or STAT3 may affect the expression of Th17 cell-related cytokines and may thus attenuate valvular damage due to RHd.

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Section: Discussionmentioning

confidence: 97%

Interference with the expression of S1PR1 or STAT3 attenuates valvular damage due to rheumatic heart disease

Xian

Chen

et al. 2021

Int J Mol Med

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“…The results of our current study also showed that the RHD group also had down-regulated S1PR1 expression and increased STAT3 phosphorylation level compared to the control group. However, some studies have reported that up-regulation of S1PR1 expression increases the phosphorylation of STAT3 [23,42], but these studies are not about RHD. Combined with the uncertainty of the expression of S1PR1 in different heart diseases mentioned above, it can be concluded that the expression level of S1PR1…”

Section: Discussionmentioning

confidence: 98%

Intervening in the S1PR1/STAT3 Signaling Pathway Attenuates Valvular Damage Due to Rheumatic Heart Disease

Xian

Chen

et al. 2020

Preprint

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Background: Rheumatic heart disease (RHD) affects many patients every year, but its pathogenesis is still unclear. Recent studies have found that the sphingosine 1-phosphate receptor 1 (S1PR1)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is involved in valvular damage by promoting the differentiation of T helper 17 (Th17) cells during the development of valvular damage caused by RHD. In this work, we investigated whether altering the S1PR1/STAT3 signaling pathway attenuates valvular damage due to RHD. Methods: Inactivated Group A streptococci (GAS) was used to establish the RHD rat model. Recombinant adeno-associated virus (serotype 9) vectors carrying the S1PR1 overexpression sequence was used to overexpress the expression of S1PR1. STAT3-small interfering RNA (STAT3-siRNA) was used to inhibit the expression of STAT3. Reverse transcription-quantitative PCR (RT-qPCR) was used to detect the mRNA expression of S1PR1, STAT3, collagen type III α1 chain (Col3a1) and fibroblast-specific protein 1 (FSP1). Western blotting (WB) and immunohistochemistry were used to detect the protein expression of S1PR1, STAT3, phosphorylated (p-) STAT3, retinoic acid-related orphan receptor gamma T (RORγt). Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were used to detect the levels of interleukin (IL)-6 and IL-17. Haematoxylin and eosin (H&E) staining and Sirius red staining were used to evaluate the degree of inflammation and fibrosis in valve tissues.Results: The expression of S1PR1 in valve tissues of RHD model rats was decreased. The levels of IL-6 and IL-17 in valves and serum of RHD model rats were increased as well as an increase of p-STAT3. The degree of valvular inflammation and fibrosis of RHD model rats was increased. Overexpression of S1PR1 and Inhibition of STAT3 overexpressed S1PR1 expression and decreased STAT3 expression respectively and reduced the total amount of p-STAT3, resulting in decreased expression of IL-6, IL-17 and RORγt and reduced the degree of valvular inflammatory and fibrosis. Conclusions: These results suggest that the S1PR1/STAT3 signaling pathway is involved in regulating the Th17 cell-related cytokines during the vavular damage due to RHD, and altering the S1PR1/STAT3 signaling pathway could affect the expression of Th17 cell-related cytokines then attenuate the vavular damage due to RHD.

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“…This protocol was performed as described previously ( Silva et al, 2014 ; Lenhare et al, 2017 ; Silva et al, 2018 ). Briefly, the mice were acclimated to swimming for 2 days (10 min/24 h).…”

Section: Methodsmentioning

confidence: 99%

Acute exercise reduces feeding by activating IL-6/Tubby axis in the mouse hypothalamus

et al. 2022

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Background: Acute exercise contributes to decreased feeding through leptin and interleukin/Janus kinase 2/signal transducers and activators of transcription 3 (IL-6/JAK2/STAT3) signaling. Considering the pleiotropic use of substrates by JAK2 and that JAK2 can phosphorylate the Tubby protein (TUB) in CHO-IR cells, we speculated that acute exercise can activate the IL-6/JAK2/TUB pathway to decrease food intake.Aims: We investigated whether acute exercise induced tyrosine phosphorylation and the association of TUB and JAK2 in the hypothalamus and if IL-6 is involved in this response, whether acute exercise increases the IL-6/TUB axis to regulate feeding, and if leptin has an additive effect over this mechanism.Methods: We applied a combination of genetic, pharmacological, and molecular approaches.Key findings: The in vivo experiments showed that acute exercise increased the tyrosine phosphorylation and association of JAK2/TUB in the hypothalamus, which reduced feeding. This response was dependent on IL-6. Leptin had no additive effect on this mechanism.Significance: The results of this study suggest a novel hypothalamic pathway by which IL-6 released by exercise regulates feeding and reinforces the beneficial effects of exercise.

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Exercise activates the hypothalamic S1PR1–STAT3 axis through the central action of interleukin 6 in mice

Cited by 11 publications

References 37 publications

Interference with the expression of S1PR1 or STAT3 attenuates valvular damage due to rheumatic heart disease

Interference with the expression of S1PR1 or STAT3 attenuates valvular damage due to rheumatic heart disease

Intervening in the S1PR1/STAT3 Signaling Pathway Attenuates Valvular Damage Due to Rheumatic Heart Disease

Acute exercise reduces feeding by activating IL-6/Tubby axis in the mouse hypothalamus

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