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- Title
TGFβ2 and TGFβ3 isoforms drive fibrotic disease pathogenesis.
- Authors
Sun, Tianhe; Huang, Zhiyu; Liang, Wei-Ching; Yin, Jianping; Lin, Wei Yu; Wu, Jia; Vernes, Jean-Michel; Lutman, Jeff; Caplazi, Patrick; Jeet, Surinder; Wong, Tiffany; Wong, Manda; DePianto, Daryle J.; Morshead, Katrina B.; Sun, Kai-Hui; Modrusan, Zora; Vander Heiden, Jason A.; Abbas, Alexander R.; Zhang, Hua; Xu, Min
- Abstract
Narrowing down the role of TGFβ: Aberrant transforming growth factor–β (TGFβ) signaling is responsible for driving fibrogenesis in several organs, including lungs and liver. However, pan-TGFβ inhibition leads to severe side effects. TGFβ exits in three isoforms: TGFβ1, 2, and 3. Here, Sun et al. showed that TGFB2 and TGFB3 expression is increased in human fibrotic tissue and in experimental models and these two isoforms contribute to fibrosis in mouse models. The authors developed isoform-specific antibodies and showed that TGFβ2 and/or TGFβ3 inhibition had therapeutic effects in lung and liver fibrosis models, without toxicity. Isoform-specific TFGβ inhibition might be an effective therapy for safely reducing fibrogenesis. Transforming growth factor–β (TGFβ) is a key driver of fibrogenesis. Three TGFβ isoforms (TGFβ1, TGFβ2, and TGFβ3) in mammals have distinct functions in embryonic development; however, the postnatal pathological roles and activation mechanisms of TGFβ2 and TGFβ3 have not been well characterized. Here, we show that the latent forms of TGFβ2 and TGFβ3 can be activated by integrin-independent mechanisms and have lower activation thresholds compared to TGFβ1. Unlike TGFB1, TGFB2 and TGFB3 expression is increased in human lung and liver fibrotic tissues compared to healthy control tissues. Thus, TGFβ2 and TGFβ3 may play a pathological role in fibrosis. Inducible conditional knockout mice and anti-TGFβ isoform-selective antibodies demonstrated that TGFβ2 and TGFβ3 are independently involved in mouse fibrosis models in vivo, and selective TGFβ2 and TGFβ3 inhibition does not lead to the increased inflammation observed with pan-TGFβ isoform inhibition. A cocrystal structure of a TGFβ2–anti-TGFβ2/3 antibody complex reveals an allosteric isoform-selective inhibitory mechanism. Therefore, inhibiting TGFβ2 and/or TGFβ3 while sparing TGFβ1 may alleviate fibrosis without toxicity concerns associated with pan-TGFβ blockade.
- Subjects
LABORATORY mice; PATHOGENESIS; PULMONARY fibrosis; ACTIVATION energy; EMBRYOLOGY
- Publication
Science Translational Medicine, 2021, Vol 13, Issue 605, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abe0407