Histone demethylase JARID1C/KDM5C regulates Th17 cells by increasing IL-6 expression in diabetic plasmacytoid dendritic cells.

Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE

Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]-

Dendritic Cells*/immunology ; Dendritic Cells*/metabolism ; Interleukin-6*/metabolism ; Th17 Cells*/immunology ; Th17 Cells*/metabolism ; Wound Healing*/immunology; Animals ; Female ; Humans ; Male ; Mice ; Interleukin-17/metabolism ; Jumonji Domain-Containing Histone Demethylases/metabolism ; Jumonji Domain-Containing Histone Demethylases/genetics ; Mice, Inbred C57BL

Plasmacytoid dendritic cells (pDCs) are first responders to tissue injury, where they prime naive T cells. The role of pDCs in physiologic wound repair has been examined, but little is known about pDCs in diabetic wound tissue and their interactions with naive CD4+ T cells. Diabetic wounds are characterized by increased levels of inflammatory IL-17A cytokine, partly due to increased Th17 CD4+ cells. This increased IL-17A cytokine, in excess, impairs tissue repair. Here, using human tissue and murine wound healing models, we found that diabetic wound pDCs produced excess IL-6 and TGF-β and that these cytokines skewed naive CD4+ T cells toward a Th17 inflammatory phenotype following cutaneous injury. Further, we identified that increased IL-6 cytokine production by diabetic wound pDCs is regulated by a histone demethylase, Jumonji AT-rich interactive domain 1C histone demethylase (JARID1C). Decreased JARID1C increased IL-6 transcription in diabetic pDCs, and this process was regulated upstream by an IFN-I/TYK2/JAK1,3 signaling pathway. When inhibited in nondiabetic wound pDCs, JARID1C skewed naive CD4+ T cells toward a Th17 phenotype and increased IL-17A production. Together, this suggests that diabetic wound pDCs are epigenetically altered to increase IL-6 expression that then affects T cell phenotype. These findings identify a therapeutically manipulable pathway in diabetic wounds.

J Int Med Res. 2009 Sep-Oct;37(5):1528-42. (PMID: 19930861)
J Exp Med. 2005 Jul 4;202(1):135-43. (PMID: 15998792)
J Immunol. 2022 Jul 1;209(1):69-76. (PMID: 35697385)
J Allergy Clin Immunol. 2020 May;145(5):1406-1415. (PMID: 31891686)
Exp Anim. 2020 Aug 5;69(3):326-335. (PMID: 32188837)
Inflammopharmacology. 2018 Jun;26(3):685-698. (PMID: 29508109)
Eur J Immunol. 2020 Dec;50(12):1929-1940. (PMID: 32662520)
Bioinformatics. 2015 Jan 15;31(2):166-9. (PMID: 25260700)
Am J Physiol Cell Physiol. 2003 Apr;284(4):C953-61. (PMID: 12466150)
Diabetes. 2016 Mar;65(3):780-93. (PMID: 26718502)
Arterioscler Thromb Vasc Biol. 2018 May;38(5):1102-1114. (PMID: 29496661)
Ann N Y Acad Sci. 2010 Jan;1183:89-103. (PMID: 20146710)
J Immunol. 2008 Aug 15;181(4):2277-84. (PMID: 18684916)
Immunol Res. 2023 Jun;71(3):451-462. (PMID: 36595206)
Immunity. 2006 Feb;24(2):179-89. (PMID: 16473830)
JCI Insight. 2020 Mar 12;5(5):. (PMID: 32069267)
Front Immunol. 2021 Apr 19;12:664847. (PMID: 33953726)
Immunity. 2019 Aug 20;51(2):258-271.e5. (PMID: 31350176)
Nat Rev Immunol. 2008 Aug;8(8):594-606. (PMID: 18641647)
Theranostics. 2021 Aug 4;11(18):8674-8691. (PMID: 34522206)
Autoimmun Rev. 2020 Oct;19(10):102647. (PMID: 32801039)
Genome Biol. 2014;15(12):550. (PMID: 25516281)
Trends Cancer. 2017 Oct;3(10):713-725. (PMID: 28958389)
Lancet. 2005 Nov 12;366(9498):1736-43. (PMID: 16291068)
J Exp Med. 2010 Dec 20;207(13):2921-30. (PMID: 21115688)
Nature. 2022 Apr;604(7905):337-342. (PMID: 35355021)
Front Immunol. 2021 Jun 16;12:681710. (PMID: 34220830)
Physiol Rev. 2019 Jan 1;99(1):665-706. (PMID: 30475656)
J Invest Dermatol. 2002 Nov;119(5):1096-102. (PMID: 12445198)
Eur J Immunol. 2018 Sep;48(9):1445-1455. (PMID: 29879295)
Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18460-5. (PMID: 19015529)
PLoS One. 2011 Apr 07;6(4):e18410. (PMID: 21490918)
Front Immunol. 2017 Jun 01;8:635. (PMID: 28620387)
Immunology. 2015 Apr;144(4):677-86. (PMID: 25363329)
Nat Rev Immunol. 2015 Aug;15(8):471-85. (PMID: 26160613)
Exp Mol Med. 2019 Jun 20;51(6):1-17. (PMID: 31221981)
Immunity. 2011 Dec 23;35(6):958-71. (PMID: 22177923)
Diabetes. 2017 Sep;66(9):2459-2471. (PMID: 28663191)
J Immunol. 2000 Dec 1;165(11):6037-46. (PMID: 11086035)
Nat Rev Drug Discov. 2012 Oct;11(10):763-76. (PMID: 23023676)
Immunol Res. 2020 Oct;68(5):296-309. (PMID: 32827097)
Br J Pharmacol. 2014 Aug;171(15):3595-603. (PMID: 24697653)
Sci Immunol. 2020 Jul 17;5(49):. (PMID: 32680955)
J Invest Dermatol. 2020 Feb;140(2):455-464.e8. (PMID: 31344385)
JCI Insight. 2020 Sep 3;5(17):. (PMID: 32879137)
Diabetes. 2007 Jun;56(6):1630-7. (PMID: 17363741)
Nat Biotechnol. 2018 Jun;36(5):411-420. (PMID: 29608179)
J Immunol. 2016 Mar 1;196(5):2010-4. (PMID: 26826250)
Nat Immunol. 2000 Oct;1(4):305-10. (PMID: 11017101)
Acta Reumatol Port. 2018 Oct-Dec;43(4):269-278. (PMID: 30641535)
J Invest Dermatol. 2014 Jul;134(7):1828-1838. (PMID: 24441097)
Science. 1994 Jun 3;264(5164):1415-21. (PMID: 8197455)
Biol Chem. 2014 Mar;395(3):335-46. (PMID: 24184991)
Cell Mol Immunol. 2022 Nov;19(11):1251-1262. (PMID: 36127466)
Curr Protoc Neurosci. 2002 Feb;Chapter 9:Unit 9.10. (PMID: 18428569)
J Neuroimmunol. 2018 Sep 15;322:63-73. (PMID: 30049538)
PLoS One. 2017 Aug 1;12(8):e0181868. (PMID: 28763457)
Sci Adv. 2016 Nov 18;2(11):e1501662. (PMID: 28138513)
Nat Rev Immunol. 2003 Nov;3(11):900-11. (PMID: 14668806)
Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886)
J Leukoc Biol. 2003 Jun;73(6):713-21. (PMID: 12773503)
JCI Insight. 2022 May 9;7(9):. (PMID: 35358091)
Semin Cell Dev Biol. 2021 Nov;119:111-118. (PMID: 34183242)
Front Immunol. 2018 Mar 23;9:585. (PMID: 29662491)
Trends Immunol. 2006 Aug;27(8):358-61. (PMID: 16793343)
J Invest Dermatol. 2020 Aug;140(8):1546-1555.e4. (PMID: 31972249)
Diabetologia. 2005 Apr;48(4):675-86. (PMID: 15729571)
Nat Commun. 2019 Feb 1;10(1):549. (PMID: 30710091)
Life Sci. 2019 Dec 15;239:116868. (PMID: 31682847)
Arterioscler Thromb Vasc Biol. 2019 Nov;39(11):2353-2366. (PMID: 31644352)
Nat Rev Immunol. 2017 Jun;17(6):349-362. (PMID: 28436425)
Front Endocrinol (Lausanne). 2021 Nov 09;12:737276. (PMID: 34858326)
J Diabetes Res. 2021 Sep 15;2021:7945117. (PMID: 34568499)
J Clin Invest. 2020 Nov 2;130(11):5688-5702. (PMID: 32701509)
Biomed Pharmacother. 2018 May;101:287-292. (PMID: 29499402)
Eur J Immunol. 2016 Feb;46(2):390-9. (PMID: 26518995)
Clin Pediatr Endocrinol. 2021;30(1):61-64. (PMID: 33446955)
Immunity. 2019 Jan 15;50(1):37-50. (PMID: 30650380)
Pigment Cell Melanoma Res. 2018 Mar;31(2):330-336. (PMID: 29094481)
Mol Med. 2022 Dec 3;28(1):144. (PMID: 36463128)
Semin Immunopathol. 2019 May;41(3):283-297. (PMID: 30891627)
J Biochem. 2022 Dec 27;173(1):31-42. (PMID: 36205465)
Diabetes. 2015 Apr;64(4):1420-30. (PMID: 25368099)
J Immunol. 2017 Jul 1;199(1):17-24. (PMID: 28630109)

R01 HL137919 United States HL NHLBI NIH HHS; R01 DK127531 United States DK NIDDK NIH HHS; R01 HL156274 United States HL NHLBI NIH HHS; K99 DK133828 United States DK NIDDK NIH HHS; R01 DK124290 United States DK NIDDK NIH HHS; T32 AI007413 United States AI NIAID NIH HHS; R35 HL144481 United States HL NHLBI NIH HHS; R01 AR079863 United States AR NIAMS NIH HHS; R01 HL156275 United States HL NHLBI NIH HHS; F32 DK126471 United States DK NIDDK NIH HHS

Keywords: Adaptive immunity; Dendritic cells; Epigenetics; Immunology; Inflammation

0 (Interleukin-17)
0 (Interleukin-6)
EC 1.14.11.- (Jumonji Domain-Containing Histone Demethylases)
EC 1.14.11.- (KDM5C protein, human)
EC 1.14.11.- (Kdm5c protein, mouse)
0 (IL6 protein, human)
0 (interleukin-6, mouse)

Date Created: 20240624 Date Completed: 20240624 Latest Revision: 20240911

20240911

PMC11383169

10.1172/jci.insight.172959

38912581