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Interleukin 6 trans‐signaling is a critical driver of lung allograft fibrosis
Author(s) -
Wheeler David S.,
Misumi Keizo,
Walker Natalie M.,
Vittal Ragini,
Combs Michael P.,
Aoki Yoshiro,
Braeuer Russell R.,
Lama Vibha N.
Publication year - 2021
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.16417
Subject(s) - medicine , fibrosis , bronchoalveolar lavage , downregulation and upregulation , pathogenesis , inflammation , mesenchymal stem cell , lung , cancer research , peripheral blood mononuclear cell , interleukin , pulmonary fibrosis , stat3 , crosstalk , immunology , myofibroblast , phosphorylation , cytokine , pathology , microbiology and biotechnology , biology , gene , biochemistry , physics , optics , in vitro
Histopathologic examination of lungs afflicted by chronic lung allograft dysfunction (CLAD) consistently shows both mononuclear cell (MNC) inflammation and mesenchymal cell (MC) fibroproliferation. We hypothesize that interleukin 6 (IL‐6) trans‐signaling may be a critical mediator of MNC‐MC crosstalk and necessary for the pathogenesis of CLAD. Bronchoalveolar lavage (BAL) fluid obtained after the diagnosis of CLAD has approximately twofold higher IL‐6 and soluble IL‐6 receptor (sIL‐6R) levels compared to matched pre‐CLAD samples. Human BAL‐derived MCs do not respond to treatment with IL‐6 alone but have rapid and prolonged JAK2‐mediated STAT3 Tyr705 phosphorylation when exposed to the combination of IL‐6 and sIL‐6R. STAT3 phosphorylation within MCs upregulates numerous genes causing increased invasion and fibrotic differentiation. MNC, a key source of both IL‐6 and sIL‐6R, produce minimal amounts of these proteins at baseline but significantly upregulate production when cocultured with MCs. Finally, the use of an IL‐6 deficient recipient in a murine orthotopic transplant model of CLAD reduces allograft fibrosis by over 50%. Taken together these results support a mechanism where infiltrating MNCs are stimulated by resident MCs to release large quantities of IL‐6 and sIL‐6R which then feedback onto the MCs to increase invasion and fibrotic differentiation.