Interleukin 6 trans-signaling is a critical driver of lung allograft fibrosis.
animal models: murine
basic (laboratory) research / science
bronchiolitis obliterans (BOS)
cellular biology
cytokines / cytokine receptors
fibrosis
lung transplantation / pulmonology
translational research / science
Journal
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
ISSN: 1600-6143
Titre abrégé: Am J Transplant
Pays: United States
ID NLM: 100968638
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
revised:
06
11
2020
received:
01
06
2020
accepted:
23
11
2020
pubmed:
30
11
2020
medline:
10
8
2021
entrez:
29
11
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33249747
doi: 10.1111/ajt.16417
pmc: PMC8809084
mid: NIHMS1651117
pii: S1600-6135(22)08625-7
doi:
Substances chimiques
Interleukin-6
0
Receptors, Interleukin-6
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2360-2371Subventions
Organisme : NHLBI NIH HHS
ID : T32 HL007749
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL118017
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL094622
Pays : United States
Informations de copyright
© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.
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