AdipoR1 promotes pathogenic Th17 differentiation by regulating mitochondrial function through FUNDC1

Abstract

Adiponectin receptor 1 (Adipor1) deficiency has been shown to inhibit Th17 cell differentiation and reduce joint inflammation and bone erosion in antigen-induced arthritis mice. Additional emerging evidence indicates that Th17 cells may differentiate into pathogenic (pTh17) and non-pathogenic (npTh17) cells, with the pTh17 cells playing a crucial role in numerous autoimmune and inflammatory conditions. In the current study, we found that Adipor1 deficiency inhibited pTh17 differentiation in vitro and induced mitochondrial dysfunction in pTh17 cells. RNA sequencing demonstrated a significant increase in the expression levels of Fundc1, a gene related to mitochondrial function, in Adipor1-deficient CD4⁺ T cells. Fundc1 knockdown in Adipor1-deficient CD4⁺ T cells partially reversed the effects of Adipor1 deficiency on mitochondrial function and pTh17 differentiation. In conclusion, the current study demonstrated a novel role of Adipor1 in regulating mitochondrial function via Fundc1 to promote pTh17 cell differentiation, providing some insight into potential therapeutic targets for autoimmune and inflammatory diseases.

Keywords

AdipoR1 / pTh17 / FUNDC1 / mitochondrial function

Fundings

This research received funding from the National Natural Science Foundation of China (Grant No. 82071827) and the Jiangsu Province Natural Science Foundation (Grant No. BK20210963).

Acknowledgments

We acknowledge and appreciate Prof. Fang Wang and Prof. Meijuan Zou for their experimental technical support.

References

[1] Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation[J]. J Exp Med, 2005, 201(2): 233-240. doi: 10.1084/jem.20041257

[2] Zhou L, Ivanov II, Spolski R, et al. IL-6 programs T_H-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways[J]. Nat Immunol, 2007, 8(9): 967-974. doi: 10.1038/ni1488

[3] Wu B, Wan Y. Molecular control of pathogenic Th17 cells in autoimmune diseases[J]. Int Immunopharmacol, 2020, 80: 106187. doi: 10.1016/j.intimp.2020.106187

[4] Lin J, Tang J, Lin J, et al. YY1 regulation by miR-124-3p promotes Th17 cell pathogenicity through interaction with T-bet in rheumatoid arthritis[J]. JCI Insight, 2021, 6(22): e149985. doi: 10.1172/jci.insight.149985

[5] Stockinger B, Omenetti S. The dichotomous nature of T helper 17 cells[J]. Nat Rev Immunol, 2017, 17(9): 535-544. doi: 10.1038/nri.2017.50

[6] Lee Y, Awasthi A, Yosef N, et al. Induction and molecular signature of pathogenic T_H17 cells[J]. Nat Immunol, 2012, 13(10): 991-999. doi: 10.1038/ni.2416

[7] McGeachy MJ, Bak-Jensen KS, Chen Y, et al. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T_H-17 cell-mediated pathology[J]. Nat Immunol, 2007, 8(12): 1390-1397. doi: 10.1038/ni1539

[8] Veldhoen M, Hocking RJ, Atkins CJ, et al. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells[J]. Immunity, 2006, 24(2): 179-189. doi: 10.1016/j.immuni.2006.01.001

[9] Ghoreschi K, Laurence A, Yang XP, et al. T helper 17 cell heterogeneity and pathogenicity in autoimmune disease[J]. Trends Immunol, 2011, 32(9): 395-401. doi: 10.1016/j.it.2011.06.007

[10] Gaublomme JT, Yosef N, Lee Y, et al. Single-cell genomics unveils critical regulators of Th17 cell pathogenicity[J]. Cell, 2015, 163(6): 1400-1412. doi: 10.1016/j.cell.2015.11.009

[11] Omenetti S, Bussi C, Metidji A, et al. The intestine harbors functionally distinct homeostatic tissue-resident and inflammatory Th17 cells[J]. Immunity, 2019, 51(1): 77-89.e6. doi: 10.1016/j.immuni.2019.05.004

[12] Wang C, Yosef N, Gaublomme J, et al. CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity[J]. Cell, 2015, 163(6): 1413-1427. doi: 10.1016/j.cell.2015.10.068

[13] Toghi M, Bitarafan S, Ghafouri-Fard S. Pathogenic Th17 cells in autoimmunity with regard to rheumatoid arthritis[J]. Pathol Res Pract, 2023, 250: 154818. doi: 10.1016/j.prp.2023.154818

[14] Khoramipour K, Chamari K, Hekmatikar AA, et al. Adiponectin: structure, physiological functions, role in diseases, and effects of nutrition[J]. Nutrients, 2021, 13(4): 1180. doi: 10.3390/nu13041180

[15] Tan W, Wang F, Zhang M, et al. High adiponectin and adiponectin receptor 1 expression in synovial fluids and synovial tissues of patients with rheumatoid arthritis[J]. Semin Arthritis Rheum, 2009, 38(6): 420-427. doi: 10.1016/j.semarthrit.2008.01.017

[16] Sun X, Feng X, Tan W, et al. Adiponectin exacerbates collagen-induced arthritis via enhancing Th17 response and prompting RANKL expression[J]. Sci Rep, 2015, 5: 11296. doi: 10.1038/srep11296

[17] Zhang Q, Wang L, Jiang J, et al. Critical role of adipor1 in regulating Th17 cell differentiation through modulation of HIF-1α-dependent glycolysis[J]. Front Immunol, 2020, 11: 2040. doi: 10.3389/fimmu.2020.02040

[18] Giacomello M, Pyakurel A, Glytsou C, et al. The cell biology of mitochondrial membrane dynamics[J]. Nat Rev Mol Cell Biol, 2020, 21(4): 204-224. doi: 10.1038/s41580-020-0210-7

[19] Kaufmann U, Kahlfuss S, Yang J, et al. Calcium signaling controls pathogenic Th17 cell-mediated inflammation by regulating mitochondrial function[J]. Cell Metab, 2019, 29(5): 1104-1118.e6. doi: 10.1016/j.cmet.2019.01.019

[20] Shin B, Benavides GA, Geng J, et al. Mitochondrial oxidative phosphorylation regulates the fate decision between pathogenic Th17 and regulatory T cells[J]. Cell Rep, 2020, 30(6): 1898-1909.e4. doi: 10.1016/j.celrep.2020.01.022

[21] Chen M, Chen Z, Wang Y, et al. Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy[J]. Autophagy, 2016, 12(4): 689-702. doi: 10.1080/15548627.2016.1151580

[22] Cai C, Guo Z, Chang X, et al. Empagliflozin attenuates cardiac microvascular ischemia/reperfusion through activating the AMPKα1/ULK1/FUNDC1/mitophagy pathway[J]. Redox Biol, 2022, 52: 102288. doi: 10.1016/j.redox.2022.102288

[23] Zhou H, Li D, Zhu P, et al. Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPARγ/FUNDC1/mitophagy pathways[J]. J Pineal Res, 2017, 63(4): e12438. doi: 10.1111/jpi.12438

[24] Wu S, Lu Q, Wang Q, et al. Binding of FUN14 domain containing 1 with inositol 1, 4, 5-trisphosphate receptor in mitochondria-associated endoplasmic reticulum membranes maintains mitochondrial dynamics and function in hearts in vivo[J]. Circulation, 2017, 136(23): 2248-2266. doi: 10.1161/CIRCULATIONAHA.117.030235

[25] Mazzoni A, Maggi L, Liotta F, et al. Biological and clinical significance of T helper 17 cell plasticity[J]. Immunology, 2019, 158(4): 287-295. doi: 10.1111/imm.13124

[26] Zhang K, Guo Y, Ge Z, et al. Adiponectin suppresses T helper 17 cell differentiation and limits autoimmune CNS inflammation via the SIRT1/PPARγ/RORγt pathway[J]. Mol Neurobiol, 2017, 54(7): 4908-4920. doi: 10.1007/s12035-016-0036-7

[27] Jung MY, Kim HS, Hong HJ, et al. Adiponectin induces dendritic cell activation via PLCγ/JNK/NF-κB pathways, leading to Th1 and Th17 polarization[J]. J Immunol, 2012, 188(6): 2592-2601. doi: 10.4049/jimmunol.1102588

[28] Niu T, Cheng L, Wang H, et al. KS23, a novel peptide derived from adiponectin, inhibits retinal inflammation and downregulates the proportions of Th1 and Th17 cells during experimental autoimmune uveitis[J]. J Neuroinflammation, 2019, 16(1): 278. doi: 10.1186/s12974-019-1686-y

[29] Murayama MA, Chi HH, Matsuoka M, et al. The CTRP3-AdipoR2 axis regulates the development of experimental autoimmune encephalomyelitis by suppressing Th17 cell differentiation[J]. Front Immunol, 2021, 12: 607346. doi: 10.3389/fimmu.2021.607346

[30] Liu L, Feng D, Chen G, et al. Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells[J]. Nat Cell Biol, 2012, 14(2): 177-185. doi: 10.1038/ncb2422

[31] Chen G, Han Z, Feng D, et al. A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy[J]. Mol Cell, 2014, 54(3): 362-377. doi: 10.1016/j.molcel.2014.02.034

[32] Wu S, Lu Q, Ding Y, et al. Hyperglycemia-driven inhibition of AMP-activated protein kinase α2 induces diabetic cardiomyopathy by promoting mitochondria-associated endoplasmic reticulum membranes in vivo[J]. Circulation, 2019, 139(16): 1913-1936. doi: 10.1161/CIRCULATIONAHA.118.033552

[33] Iwabu M, Yamauchi T, Okada-Iwabu M, et al. Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca²⁺ and AMPK/SIRT1[J]. Nature, 2010, 464(7293): 1313-1319. doi: 10.1038/nature08991

[34] Kanno Y, Ishisaki A, Kawashita E, et al. uPA attenuated LPS-induced inflammatory osteoclastogenesis through the plasmin/PAR-1/Ca²⁺/CaMKK/AMPK axis[J]. Int J Biol Sci, 2016, 12(1): 63-71. doi: 10.7150/ijbs.12690