TY - JOUR
T1 - Canonical and noncanonical regulatory roles for JAK2 in the pathogenesis of rheumatoid arthritis-associated interstitial lung disease and idiopathic pulmonary fibrosis
AU - Wang, Shaohua
AU - Liu, Mengfei
AU - Li, Xiujuan
AU - Zhang, Jie
AU - Wang, Faping
AU - Zhang, Chujie
AU - Roden, Anja
AU - Ryu, Jay H.
AU - Warrington, Kenneth J.
AU - Sun, Jie
AU - Matteson, Eric L.
AU - Tschumperlin, Daniel J.
AU - Vassallo, Robert
N1 - Funding Information:
The study was funded by a research grant from the Hurvis Foundation, the Rheumatology Research Foundation, Pfizer, and Mayo Clinic support.
Funding Information:
R. Vassallo has received research grant funding from Pfizer, Bristol Myers Squibb, and Sun Pharma. S. Wang, M. Liu, X. Li, J. Zhang, F. Wang, C. Zhang, A. Roden, J. H. Ryu, K. J. Warrington, J. Sun, E. L. Matteson, and D. J. Tschumperlin have nothing to disclose.
Publisher Copyright:
© 2022 Federation of American Societies for Experimental Biology.
PY - 2022/6
Y1 - 2022/6
N2 - Idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-associated interstitial lung disease (RA-ILD) are two fibrotic interstitial lung diseases that share the usual interstitial pneumonia (UIP) injury pattern. Here, we report that RNA sequencing of lung biopsies from patients with RA-ILD and IPF revealed shared and distinct disease-causing pathways. Analysis of transcriptomic data identified a JAK2 related JAK/STAT signaling pathway gene signature that distinguishes RA-UIP from idiopathic UIP. This was further confirmed by immunohistostaining, which identified JAK2 phosphorylation with two distinct forms of activation: a cytoplasmic form of JAK2 activation in most IPF cases (13/20) and a nuclear form of p-JAK2 in RA-UIP (5/5) and a minority of IPF (6/20) cases. Further immunohistostaining identified STAT5A&B as the downstream transcriptional activator for JAK2-mediated canonical signal transduction and phosphorylation of Tyr41 on histone H3 (H3Y41ph) as the downstream epigenetic regulation site for JAK2-mediated noncanonical signal transduction. Gene Set Enrichment Analysis (GSEA) of the RNA-Seq data further supported this shared pathogenic mechanism for the two diseases with the enrichment of STAT5A&B target gene sets as well as the JAK2 regulated H3Y41ph target gene set. This regulatory role of JAK2 in the pathogenesis of pulmonary fibrosis was further demonstrated by the attenuation of bleomycin-induced murine pulmonary fibrosis using a JAK2-selective pharmacological inhibitor CEP33779. In vitro studies with normal and IPF derived lung fibroblasts revealed a central role for JAK2 as an essential intermediary molecule in TGF-β-mediated myofibroblast trans-differentiation, proliferation, and extracellular matrix protein production. These observations support a crucial role for JAK2 as an intermediary molecule in fibrotic lung disease development.
AB - Idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-associated interstitial lung disease (RA-ILD) are two fibrotic interstitial lung diseases that share the usual interstitial pneumonia (UIP) injury pattern. Here, we report that RNA sequencing of lung biopsies from patients with RA-ILD and IPF revealed shared and distinct disease-causing pathways. Analysis of transcriptomic data identified a JAK2 related JAK/STAT signaling pathway gene signature that distinguishes RA-UIP from idiopathic UIP. This was further confirmed by immunohistostaining, which identified JAK2 phosphorylation with two distinct forms of activation: a cytoplasmic form of JAK2 activation in most IPF cases (13/20) and a nuclear form of p-JAK2 in RA-UIP (5/5) and a minority of IPF (6/20) cases. Further immunohistostaining identified STAT5A&B as the downstream transcriptional activator for JAK2-mediated canonical signal transduction and phosphorylation of Tyr41 on histone H3 (H3Y41ph) as the downstream epigenetic regulation site for JAK2-mediated noncanonical signal transduction. Gene Set Enrichment Analysis (GSEA) of the RNA-Seq data further supported this shared pathogenic mechanism for the two diseases with the enrichment of STAT5A&B target gene sets as well as the JAK2 regulated H3Y41ph target gene set. This regulatory role of JAK2 in the pathogenesis of pulmonary fibrosis was further demonstrated by the attenuation of bleomycin-induced murine pulmonary fibrosis using a JAK2-selective pharmacological inhibitor CEP33779. In vitro studies with normal and IPF derived lung fibroblasts revealed a central role for JAK2 as an essential intermediary molecule in TGF-β-mediated myofibroblast trans-differentiation, proliferation, and extracellular matrix protein production. These observations support a crucial role for JAK2 as an intermediary molecule in fibrotic lung disease development.
KW - Janus kinase 2
KW - STAT3 transcription factor
KW - STAT5 transcription factor
KW - idiopathic pulmonary fibrosis
KW - interstitial lung disease
KW - rheumatoid arthritis
UR - http://www.scopus.com/inward/record.url?scp=85130005207&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85130005207&partnerID=8YFLogxK
U2 - 10.1096/fj.202101436R
DO - 10.1096/fj.202101436R
M3 - Article
C2 - 35522243
AN - SCOPUS:85130005207
SN - 0892-6638
VL - 36
JO - FASEB Journal
JF - FASEB Journal
IS - 6
M1 - e22336
ER -