Cln 3-requiring 9 is a negative regulator of Th17 pathway-driven inflammation in anti-glomerular basement membrane glomerulonephritis.
T helper 17 (Th17) lymphocytes promote renal inflammation in anti-glomerular basement membrane glomerulonephritis (anti-GBM GN), and signal transducer and activator of transcription 3 (STAT3) mediates activation of Th17 lymphocytes by IL-6 and transforming growth factor-β (TGF-β). Cln 3-requiring 9 (Ctr9), a subunit of RNA polymerase-associated factor complex (PAFc), regulates the transcription of IL-6/STAT3-dependent genes. Here, we investigated the role of Ctr9 in regulating Th17-driven inflammation in anti-GBM GN. In mice, STAT3β or IL-17 knockout ameliorated anti-GBM autoantibody-induced renal injury. This phenomenon was associated with decreases in retinoic acid receptor-related orphan receptor γt (RORγt), IL-17, phosphorylated STAT3, and proinflammatory cytokines. Compared with wild-type mice, Ctr9 increased in both STAT3β(-/-) and IL-17(-/-) mice injected with anti-GBM IgG, showing a negative correlation with Th17-related transcripts. Small interfering RNA (siRNA)-mediated knockdown of Ctr9 in intrarenal lymphocytes further upregulated Th17-related transcripts, consistent with repression of Th17 differentiation by Ctr9. Interestingly, Ctr9 was also expressed in human and mouse mesangial cells and downregulated in response to anti-GBM IgG or to TGF-β plus IL-17. Ctr9 in mesangial cells was even more repressed in the presence of both anti-GBM IgG and Th17-activating cytokines. Consistent with these findings, renal biopsies obtained from patients with anti-GBM GN showed consistent downregulation of Ctr9 and upregulation of phosphorylated STAT3 and IL-17 in the glomerulus. We conclude that Ctr9 is a negative regulator of Th17 differentiation in anti-GBM GN and repressed by anti-GBM IgG and IL-17 in mesangial cells.
Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea;
Hajeong
H
Lee
Nephrology Clinic, National Cancer Center Hospital, Seoul, Republic of Korea;
Jae Wook
JW
Lee
Department of Medical Science, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Dongguk University Medical Center, Gyeongju, Republic of Korea;
Kyung Don
KD
Yoo
Life Science, Pohang University of Science and Technology, Pohang, Republic of Korea;
Joo-Yeon
JY
Yoo
Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea;
Jung Pyo
JP
Lee
Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Kidney Research Institute, Seoul National University, Seoul, Republic of Korea; and.
Dong Ki
DK
Kim
Nephrology Clinic, National Cancer Center Hospital, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul, Republic of Korea.
Ho Jun
HJ
Chin
Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Department of Medical Science, Seoul National University College of Medicine, Seoul, Republic of Korea; Kidney Research Institute, Seoul National University, Seoul, Republic of Korea; and.
Yon Su
YS
Kim
Kidney Research Institute, Seoul National University, Seoul, Republic of Korea; and ysh5794@gmail.com.
Seung Hee
SH
Yang
D000818:Animals; D050533:Glomerular Basement Membrane / Q000378:metabolism* / Q000473:pathology; D005921:Glomerulonephritis / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D020381:Interleukin-17 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D050527:Mesangial Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism
D020381:Interleukin-17; D009687:Nuclear Proteins; D010750:Phosphoproteins; D050796:STAT3 Transcription Factor
Ctr9; STAT3; Th17 pathway; anti-glomerular basement membrane glomerulonephritis