Frontiers in Immunology (Feb 2024)
IL11-mediated stromal cell activation may not be the master regulator of pro-fibrotic signaling downstream of TGFβ
- Yunhao Tan,
- Kenta Mosallanejad,
- Qingxiu Zhang,
- Stephen O’Brien,
- Meghan Clements,
- Stuart Perper,
- Sarah Wilson,
- Sudiksha Chaulagain,
- Jing Wang,
- Mary Abdalla,
- Helen Al-Saidi,
- Danyal Butt,
- Anca Clabbers,
- Kwasi Ofori,
- Beth Dillon,
- Bohdan Harvey,
- John Memmott,
- Christopher Negron,
- David Winarta,
- Catherine Tan,
- Amlan Biswas,
- Feng Dong,
- Vanessa Morales-Tirado,
- Xiaoqing Lu,
- Gurminder Singh,
- Michael White,
- Shanna Ashley,
- Heather Knight,
- Susan Westmoreland,
- Lucy Phillips,
- Tracy Carr,
- Lauren Reinke-Breen,
- Rajeeva Singh,
- Jianwen Xu,
- Kan Wu,
- Lisa Rinaldi,
- Brian Stoll,
- Yupeng David He,
- Lisa Hazelwood,
- Jozsef Karman,
- Andrew McCluskey,
- William Stine,
- Ivan Correia,
- Stephen Gauld,
- Marc C. Levesque,
- Geertruida Veldman,
- Cedric Hubeau,
- Timothy Radstake,
- Ramkrishna Sadhukhan,
- Edda Fiebiger
Affiliations
- Yunhao Tan
- AbbVie Cambridge Research Center, Cambridge, MA, United States
- Kenta Mosallanejad
- AbbVie Cambridge Research Center, Cambridge, MA, United States
- Qingxiu Zhang
- AbbVie Cambridge Research Center, Cambridge, MA, United States
- Stephen O’Brien
- AbbVie Bioresearch Center, Worcester, MA, United States
- Meghan Clements
- AbbVie Bioresearch Center, Worcester, MA, United States
- Stuart Perper
- AbbVie Bioresearch Center, Worcester, MA, United States
- Sarah Wilson
- AbbVie Bioresearch Center, Worcester, MA, United States
- Sudiksha Chaulagain
- AbbVie Cambridge Research Center, Cambridge, MA, United States
- Jing Wang
- AbbVie Bioresearch Center, Worcester, MA, United States
- Mary Abdalla
- AbbVie Bioresearch Center, Worcester, MA, United States
- Helen Al-Saidi
- AbbVie Inc., North Chicago, IL, United States
- Danyal Butt
- AbbVie Bioresearch Center, Worcester, MA, United States
- Anca Clabbers
- AbbVie Bioresearch Center, Worcester, MA, United States
- Kwasi Ofori
- AbbVie Bioresearch Center, Worcester, MA, United States
- Beth Dillon
- AbbVie Bioresearch Center, Worcester, MA, United States
- Bohdan Harvey
- AbbVie Cambridge Research Center, Cambridge, MA, United States
- John Memmott
- AbbVie Bioresearch Center, Worcester, MA, United States
- Christopher Negron
- AbbVie Bioresearch Center, Worcester, MA, United States
- David Winarta
- AbbVie Bioresearch Center, Worcester, MA, United States
- Catherine Tan
- AbbVie Cambridge Research Center, Cambridge, MA, United States
- Amlan Biswas
- AbbVie Cambridge Research Center, Cambridge, MA, United States
- Feng Dong
- AbbVie Cambridge Research Center, Cambridge, MA, United States
- Vanessa Morales-Tirado
- AbbVie Bioresearch Center, Worcester, MA, United States
- Xiaoqing Lu
- AbbVie Cambridge Research Center, Cambridge, MA, United States
- Gurminder Singh
- AbbVie Cambridge Research Center, Cambridge, MA, United States
- Michael White
- AbbVie Cambridge Research Center, Cambridge, MA, United States
- Shanna Ashley
- AbbVie Inc., North Chicago, IL, United States
- Heather Knight
- AbbVie Bioresearch Center, Worcester, MA, United States
- Susan Westmoreland
- AbbVie Bioresearch Center, Worcester, MA, United States
- Lucy Phillips
- AbbVie Bioresearch Center, Worcester, MA, United States
- Tracy Carr
- AbbVie Inc., North Chicago, IL, United States
- Lauren Reinke-Breen
- AbbVie Inc., North Chicago, IL, United States
- Rajeeva Singh
- AbbVie Bioresearch Center, Worcester, MA, United States
- Jianwen Xu
- AbbVie Bioresearch Center, Worcester, MA, United States
- Kan Wu
- AbbVie Bioresearch Center, Worcester, MA, United States
- Lisa Rinaldi
- AbbVie Bioresearch Center, Worcester, MA, United States
- Brian Stoll
- AbbVie Inc., North Chicago, IL, United States
- Yupeng David He
- AbbVie Inc., North Chicago, IL, United States
- Lisa Hazelwood
- AbbVie Inc., North Chicago, IL, United States
- Jozsef Karman
- AbbVie Bioresearch Center, Worcester, MA, United States
- Andrew McCluskey
- AbbVie Bioresearch Center, Worcester, MA, United States
- William Stine
- AbbVie Bioresearch Center, Worcester, MA, United States
- Ivan Correia
- AbbVie Bioresearch Center, Worcester, MA, United States
- Stephen Gauld
- AbbVie Inc., North Chicago, IL, United States
- Marc C. Levesque
- AbbVie Cambridge Research Center, Cambridge, MA, United States
- Geertruida Veldman
- AbbVie Bioresearch Center, Worcester, MA, United States
- Cedric Hubeau
- AbbVie Cambridge Research Center, Cambridge, MA, United States
- Timothy Radstake
- AbbVie Cambridge Research Center, Cambridge, MA, United States
- Ramkrishna Sadhukhan
- AbbVie Bioresearch Center, Worcester, MA, United States
- Edda Fiebiger
- AbbVie Cambridge Research Center, Cambridge, MA, United States
- DOI
- https://doi.org/10.3389/fimmu.2024.1293883
- Journal volume & issue
-
Vol. 15
Abstract
Fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic scleroderma (SSc), are commonly associated with high morbidity and mortality, thereby representing a significant unmet medical need. Interleukin 11 (IL11)-mediated cell activation has been identified as a central mechanism for promoting fibrosis downstream of TGFβ. IL11 signaling has recently been reported to promote fibroblast-to-myofibroblast transition, thus leading to various pro-fibrotic phenotypic changes. We confirmed increased mRNA expression of IL11 and IL11Rα in fibrotic diseases by OMICs approaches and in situ hybridization. However, the vital role of IL11 as a driver for fibrosis was not recapitulated. While induction of IL11 secretion was observed downstream of TGFβ signaling in human lung fibroblasts and epithelial cells, the cellular responses induced by IL11 was quantitatively and qualitatively inferior to that of TGFβ at the transcriptional and translational levels. IL11 blocking antibodies inhibited IL11Rα-proximal STAT3 activation but failed to block TGFβ-induced profibrotic signals. In summary, our results challenge the concept of IL11 blockade as a strategy for providing transformative treatment for fibrosis.
Keywords
