Interleukin-17 Receptor Signaling Regulates Immune Response and Slows Down Myocardial Fibrosis in Mice with Dilated Cardiomyopathy
-
Weiwei Li
,
Wei Jiao
,
Fang Li
,
Jinming Liu
,
Jie Hao
Abstract
Immune response is a significant mechanism in dilated cardiomyopathy (DCM). The interleukin-17 receptor (IL-17R) is crucial for immune response.
A DCM model was created using doxorubicin, and IL-17R was knocked down. We assessed cardiac function, histopathological changes, fibrosis proteins, myocardial injury, and inflammation levels through echocardiography, pathological staining, immunofluorescence, and Western blot, respectively. The proportions of T cell subsets in mouse spleen tissue were identified through flow cytometry. Following these steps, we detached fibroblasts from the mouse heart and knocked down IL-17R. Angiotensin II was employed to induce cell fibrosis and co-cultured with T Helper 17 (TH17) cells. We measured inflammation, collagen deposits, and fibrosis protein expression using Sirius red staining, immunofluorescence, and Western blot.
IL-17R exhibited significant expression in DCM mice. The systolic function of DCM mice significantly decreased. Myocardial fibrosis and collagen deposition in the left ventricle were markedly elevated. The levels of fibrosis proteins and pro-inflammatory factors were notably enhanced (p < 0.01). The proportion of effector CD4+ T and TH17 cells in spleen tissue noticeably increased, while the Treg cell proportion notably decreased. These indicators were significantly reversed after IL-17R knockdown. In the co-culture system, pro-inflammatory cytokines, collagen formation, and fibrosis-related protein levels increased significantly after fibrosis induction. However, the level of fibrosis and TH17/Treg cell imbalance decreased significantly after IL-17R knockdown.
The knockdown of IL-17R can reduce immune reaction, which in turn improves myocardial fibrosis and alleviates DCM cardiac function.
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15. Peng Y, Qin D, Wang Y, Gao W, Xu X. Pharmacological inhibition of ICOS attenuates the protective effect of exercise on cardiac fibrosis induced by isoproterenol. Europ J Pharmacol. 2024;965:176327.
16. Du S, Li Z, Xie X, Xu C, Shen X, Wang N, et al. IL-17 stimulates the expression of CCL2 in cardiac myocytes via Act1/TRAF6/p38MAPK-dependent AP-1 activation. Scand J Immunol. 2020;91(1):e12840.
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19. Chen L, Wei XQ, Evans B, Jiang W, Aeschlimann D. IL-23 promotes osteoclast formation by up-regulation of receptor activator of NF-kappaB (RANK) expression in myeloid precursor cells. Europ J Immunol. 2008;38(10):2845-54.
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22. Chen QQ, Ma G, Liu JF, Cai YY, Zhang JY, Wei TT, et al. Neuraminidase 1 is a driver of experimental cardiac hypertrophy. Europ Heart J. 2021;42(36):3770-82.
23. Cui Y, Li J, Zhang P, Yin D, Wang Z, Dai J, et al. B4GALT1 promotes immune escape by regulating the expression of PD-L1 at multiple levels in lung adenocarcinoma. J Exp Cin Cancer Res. 2023;42(1):146.
24. Imanaka-Yoshida K. Inflammation in myocardial disease: From myocarditis to dilated cardiomyopathy. Pathol Int. 2020;70(1):1-11.
25. Mathew T, Williams L, Navaratnam G, Rana B, Wheeler R, Collins K, et al. Diagnosis and assessment of dilated cardiomyopathy: a guideline protocol from the British Society of Echocardiography. Echo Res Practice. 2017;4(2):G1-g13.
26. Wong NR, Mohan J, Kopecky BJ, Guo S, Du L, Leid J, et al. Resident cardiac macrophages mediate adaptive myocardial remodeling. Immunity. 2021;54(9):2072-88.e7.
27. Liu M, López de Juan Abad B, Cheng K. Cardiac fibrosis: Myofibroblast-mediated pathological regulation and drug delivery strategies. Adv Drug Delivery Rev. 2021;173:504-19.
28. Frangogiannis NG. Cardiac fibrosis: Cell biological mechanisms, molecular pathways and therapeutic opportunities. Mol Aspects Med. 2019;65:70-99.
29. Laronha H, Caldeira J. Structure and Function of Human Matrix Metalloproteinases. Cells. 2020;9(5).
30. Tang Y, Si Y, Liu C, Li C, Qu L, Liu Y, et al. hUMSCs Restore Uterine Function by Inhibiting Endometrial Fibrosis via Regulation of the MMP-9/TIMP-1 Ratio in CDDP-Induced Injury Rats. Stem cells Int. 2023;2023:8014052.
31. Yang F, Luo L, Zhu ZD, Zhou X, Wang Y, Xue J, et al. Chlorogenic Acid Inhibits Liver Fibrosis by Blocking the miR-21-Regulated TGF-β1/Smad7 Signaling Pathway in Vitro and in Vivo. Fronti Pharmacol. 2017;8:929.
32. Wang SQ, Li D, Yuan Y. Long-term moderate intensity exercise alleviates myocardial fibrosis in type 2 diabetic rats via inhibitions of oxidative stress and TGF-β1/Smad pathway. J Physiological Sci. 2019;69(6):861-73.
33. Jiang Y, Chai L, Wang H, Shen X, Fasae MB, Jiao J, et al. HIV Tat Protein Induces Myocardial Fibrosis Through TGF-β1-CTGF Signaling Cascade: A Potential Mechanism of HIV Infection-Related Cardiac Manifestations. Cardiovascular Toxicol. 2021;21(12):965-72.
34. Maisch B, Pankuweit S. Inflammatory dilated cardiomyopathy: Etiology and clinical management. Herz. 2020;45(3):221-9.
35. Harding D, Chong MHA, Lahoti N, Bigogno CM, Prema R, Mohiddin SA, et al. Dilated cardiomyopathy and chronic cardiac inflammation: Pathogenesis, diagnosis and therapy. J Int Med. 2023;293(1):23-47.
36. Wang J, Han B. Dysregulated CD4+ T Cells and microRNAs in Myocarditis. Front Immunol. 2020;11:539.
37. Lu Y, Zhao N, Wu Y, Yang S, Wu Q, Dong Q, et al. Inhibition of phosphoglycerate kinase 1 attenuates autoimmune myocarditis by reprogramming CD4+ T cell metabolism. Cardiovascular Res. 2023;119(6):1377-89.
38. Mohr A, Malhotra R, Mayer G, Gorochov G, Miyara M. Human FOXP3(+) T regulatory cell heterogeneity. Clin Transl Immunology. 2018;7(1):e1005.
39. Ilatovskaya DV, Halade GV, DeLeon-Pennell KY. Adaptive immunity-driven inflammation and cardiovascular disease. Am J Physiol Heart Circ Physiol. 2019;317(6):H1254-h7.
2. Tayal U, Ware JS, Lakdawala NK, Heymans S, Prasad SK. Understanding the genetics of adult-onset dilated cardiomyopathy: what a clinician needs to know. Europ Heart J. 2021;42(24):2384-96.
3. Shi H, Yuan M, Cai J, Lan L, Wang Y, Wang W, et al. HTRA1-driven detachment of type I collagen from endoplasmic reticulum contributes to myocardial fibrosis in dilated cardiomyopathy. J Trans Med. 2024;22(1):297.
4. Biwott FK, Rao N-N, Dong C-L, Wang G-B. Weighted gene co-expression network analysis reveals similarities and differences of molecular features between dilated and ischemic cardiomyopathies. J Electronic Sci Technol. 2023;21(2):100193.
5. Heymans S, Lakdawala NK, Tschöpe C, Klingel K. Dilated cardiomyopathy: causes, mechanisms, and current and future treatment approaches. Lancet (London, England). 2023;402(10406):998-1011.
6. Ciarambino T, Menna G, Sansone G, Giordano M. Cardiomyopathies: An Overview. Int J Mol Sci. 2021;22(14).
7. Guan Z, Chen J, Wang L, Hao M, Dong X, Luo T, et al. Nuanxinkang prevents the development of myocardial infarction-induced chronic heart failure by promoting PINK1/Parkin-mediated mitophagy. Phytomedicine. 2023;108:154494.
8. López B, Ravassa S, Moreno MU, José GS, Beaumont J, González A, et al. Diffuse myocardial fibrosis: mechanisms, diagnosis and therapeutic approaches. Nat Rev Cardiol. 2021;18(7):479-98.
9. Chen X, Zhang F, Hu G, Li X, Wang L, Li C, et al. LRRC8A critically regulates myofibroblast phenotypes and fibrotic remodeling following myocardial infarction. Theranostics. 2022;12(13):5824-35.
10. Bacmeister L, Schwarzl M, Warnke S, Stoffers B, Blankenberg S, Westermann D, et al. Inflammation and fibrosis in murine models of heart failure. Basic Res Cardiol. 2019;114(3):19.
11. Rubis P, Dziewiecka E, Wisniowska-Smialek S, Banys P, Urbanczyk-Zawadzka M, Krupinski M, et al. Natural history of myocardial fibrosis in dilated cardiomyopathy. Europ Heart J. 2022;43(Supplement_2).
12. Barcena ML, Pozdniakova S, Haritonow N, Breiter P, Kühl AA, Milting H, et al. Dilated cardiomyopathy impairs mitochondrial biogenesis and promotes inflammation in an age- and sex-dependent manner. Aging. 2020;12(23):24117-33.
13. Wang E, Zhou R, Li T, Hua Y, Zhou K, Li Y, et al. The Molecular Role of Immune Cells in Dilated Cardiomyopathy. Medicina (Kaunas, Lithuania). 2023;59(7).
14. Gao RF, Li X, Xiang HY, Yang H, Lv CY, Sun XL, et al. The covalent NLRP3-inflammasome inhibitor Oridonin relieves myocardial infarction-induced myocardial fibrosis and cardiac remodeling in mice. Int Immunopharmacol. 2021;90:107133.
15. Peng Y, Qin D, Wang Y, Gao W, Xu X. Pharmacological inhibition of ICOS attenuates the protective effect of exercise on cardiac fibrosis induced by isoproterenol. Europ J Pharmacol. 2024;965:176327.
16. Du S, Li Z, Xie X, Xu C, Shen X, Wang N, et al. IL-17 stimulates the expression of CCL2 in cardiac myocytes via Act1/TRAF6/p38MAPK-dependent AP-1 activation. Scand J Immunol. 2020;91(1):e12840.
17. Crawford MP, Sinha S, Renavikar PS, Borcherding N, Karandikar NJ. CD4 T cell-intrinsic role for the T helper 17 signature cytokine IL-17: Effector resistance to immune suppression. Proc Natl Acad Sci U S A. 2020;117(32):19408-14.
18. Li X, Bechara R, Zhao J, McGeachy MJ, Gaffen SL. IL-17 receptor-based signaling and implications for disease. Nat Immunol. 2019;20(12):1594-602.
19. Chen L, Wei XQ, Evans B, Jiang W, Aeschlimann D. IL-23 promotes osteoclast formation by up-regulation of receptor activator of NF-kappaB (RANK) expression in myeloid precursor cells. Europ J Immunol. 2008;38(10):2845-54.
20. Tomczyk MM, Cheung KG, Xiang B, Tamanna N, Fonseca Teixeira AL, Agarwal P, et al. Mitochondrial Sirtuin-3 (SIRT3) Prevents Doxorubicin-Induced Dilated Cardiomyopathy by Modulating Protein Acetylation and Oxidative Stress. Circul Heart failure. 2022;15(5):e008547.
21. Liu Z, Liu X, Liu L, Wang Y, Zheng J, Li L, et al. SUMO1 regulates post-infarct cardiac repair based on cellular heterogeneity. J Pharmaceutical Analysis. 2023;13(2):170-86.
22. Chen QQ, Ma G, Liu JF, Cai YY, Zhang JY, Wei TT, et al. Neuraminidase 1 is a driver of experimental cardiac hypertrophy. Europ Heart J. 2021;42(36):3770-82.
23. Cui Y, Li J, Zhang P, Yin D, Wang Z, Dai J, et al. B4GALT1 promotes immune escape by regulating the expression of PD-L1 at multiple levels in lung adenocarcinoma. J Exp Cin Cancer Res. 2023;42(1):146.
24. Imanaka-Yoshida K. Inflammation in myocardial disease: From myocarditis to dilated cardiomyopathy. Pathol Int. 2020;70(1):1-11.
25. Mathew T, Williams L, Navaratnam G, Rana B, Wheeler R, Collins K, et al. Diagnosis and assessment of dilated cardiomyopathy: a guideline protocol from the British Society of Echocardiography. Echo Res Practice. 2017;4(2):G1-g13.
26. Wong NR, Mohan J, Kopecky BJ, Guo S, Du L, Leid J, et al. Resident cardiac macrophages mediate adaptive myocardial remodeling. Immunity. 2021;54(9):2072-88.e7.
27. Liu M, López de Juan Abad B, Cheng K. Cardiac fibrosis: Myofibroblast-mediated pathological regulation and drug delivery strategies. Adv Drug Delivery Rev. 2021;173:504-19.
28. Frangogiannis NG. Cardiac fibrosis: Cell biological mechanisms, molecular pathways and therapeutic opportunities. Mol Aspects Med. 2019;65:70-99.
29. Laronha H, Caldeira J. Structure and Function of Human Matrix Metalloproteinases. Cells. 2020;9(5).
30. Tang Y, Si Y, Liu C, Li C, Qu L, Liu Y, et al. hUMSCs Restore Uterine Function by Inhibiting Endometrial Fibrosis via Regulation of the MMP-9/TIMP-1 Ratio in CDDP-Induced Injury Rats. Stem cells Int. 2023;2023:8014052.
31. Yang F, Luo L, Zhu ZD, Zhou X, Wang Y, Xue J, et al. Chlorogenic Acid Inhibits Liver Fibrosis by Blocking the miR-21-Regulated TGF-β1/Smad7 Signaling Pathway in Vitro and in Vivo. Fronti Pharmacol. 2017;8:929.
32. Wang SQ, Li D, Yuan Y. Long-term moderate intensity exercise alleviates myocardial fibrosis in type 2 diabetic rats via inhibitions of oxidative stress and TGF-β1/Smad pathway. J Physiological Sci. 2019;69(6):861-73.
33. Jiang Y, Chai L, Wang H, Shen X, Fasae MB, Jiao J, et al. HIV Tat Protein Induces Myocardial Fibrosis Through TGF-β1-CTGF Signaling Cascade: A Potential Mechanism of HIV Infection-Related Cardiac Manifestations. Cardiovascular Toxicol. 2021;21(12):965-72.
34. Maisch B, Pankuweit S. Inflammatory dilated cardiomyopathy: Etiology and clinical management. Herz. 2020;45(3):221-9.
35. Harding D, Chong MHA, Lahoti N, Bigogno CM, Prema R, Mohiddin SA, et al. Dilated cardiomyopathy and chronic cardiac inflammation: Pathogenesis, diagnosis and therapy. J Int Med. 2023;293(1):23-47.
36. Wang J, Han B. Dysregulated CD4+ T Cells and microRNAs in Myocarditis. Front Immunol. 2020;11:539.
37. Lu Y, Zhao N, Wu Y, Yang S, Wu Q, Dong Q, et al. Inhibition of phosphoglycerate kinase 1 attenuates autoimmune myocarditis by reprogramming CD4+ T cell metabolism. Cardiovascular Res. 2023;119(6):1377-89.
38. Mohr A, Malhotra R, Mayer G, Gorochov G, Miyara M. Human FOXP3(+) T regulatory cell heterogeneity. Clin Transl Immunology. 2018;7(1):e1005.
39. Ilatovskaya DV, Halade GV, DeLeon-Pennell KY. Adaptive immunity-driven inflammation and cardiovascular disease. Am J Physiol Heart Circ Physiol. 2019;317(6):H1254-h7.
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| Issue | Articles in Press | |
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| Cardiomyopathy Fibrosis Immunity Interleukin-17 T helper 17 cells | ||
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How to Cite
1.
Li W, Jiao W, Li F, Liu J, Hao J. Interleukin-17 Receptor Signaling Regulates Immune Response and Slows Down Myocardial Fibrosis in Mice with Dilated Cardiomyopathy. Iran J Allergy Asthma Immunol. 2025;:1-19.
