IL-10 deficiency aggravates cell senescence and accelerates BLM-induced pulmonary fibrosis in aged mice via PTEN/AKT/ERK pathway.

Autor: Li Y; Department of Emergency Medicine and Critical Care, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.; Research Center for Translational Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China.; Department of Respiratory and Critical Care Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China., Yin H; Research Center for Translational Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China.; Department of Thoracic Surgery, The First Affiliated Hospital of Shaoyang University, Shaoyang, 422000, China., Yuan H; Research Center for Translational Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China., Wang E; Research Center for Translational Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China., Wang C; Department of Emergency Medicine and Critical Care, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China., Li H; Department of Emergency Medicine and Critical Care, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China., Geng X; Research Center for Translational Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China., Zhang Y; Department of Emergency Medicine and Critical Care, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China. yingzhang1234567@qq.com., Bai J; Department of Emergency Medicine and Critical Care, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China. baijianwen1019@163.com.
Jazyk: angličtina
Zdroj: BMC pulmonary medicine [BMC Pulm Med] 2024 Sep 11; Vol. 24 (1), pp. 443. Date of Electronic Publication: 2024 Sep 11.
DOI: 10.1186/s12890-024-03260-x
Abstrakt: Background: Pulmonary fibrosis (PF) is an aging-related progressive lung disorder. The aged lung undergoes functional and structural changes termed immunosenescence and inflammaging, which facilitate the occurrence of fibrosis. Interleukin-10 (IL-10) is a potent anti-inflammatory and immunoregulatory cytokine, yet it remains unclear how IL-10 deficiency-induced immunosenescence participates in the development of PF.
Methods: Firstly we evaluated the susceptibility to fibrosis and IL-10 expression in aged mice. Then 13-month-old wild-type (WT) and IL-10 knockout (KO) mice were subjected to bleomycin(BLM) and analyzed senescence-related markers by PCR, western blot and immunohistochemistry staining of p16, p21, p53, as well as DHE and SA-β-gal staining. We further compared 18-month-old WT mice with 13-month-old IL-10KO mice to assess aging-associated cell senescence and inflamation infiltration in both lung and BALF. Moreover, proliferation and apoptosis of alveolar type 2 cells(AT2) were evaluated by FCM, immunofluorescence, TUNEL staining, and TEM analysis. Recombinant IL-10 (rIL-10) was also administered intratracheally to evaluate its therapeutic potential and related mechanism. For the in vitro experiments, 10-week-old naïve pramily lung fibroblasts(PLFs) were treated with the culture medium of 13-month PLFs derived from WT, IL-10KO, or IL-10KO + rIL-10 respectively, and examined the secretion of senescence-associated secretory phenotype (SASP) factors and related pathways.
Results: The aged mice displayed increased susceptibility to fibrosis and decreased IL-10 expression. The 13-month-old IL-10KO mice exhibited significant exacerbation of cell senescence compared to their contemporary WT mice, and even more severe epithelial-mesenchymal transition (EMT) than that of 18 month WT mice. These IL-10 deficient mice showed heightened inflammatory responses and accelerated PF progression. Intratracheal administration of rIL-10 reduced lung CD45 + cell infiltration by 15%, including a 6% reduction in granulocytes and a 10% reduction in macrophages, and increased the proportion of AT2 cells by approximately 8%. Additionally, rIL-10 significantly decreased α-SMA and collagen deposition, and reduced the expression of senescence proteins p16 and p21 by 50% in these mice. In vitro analysis revealed that conditioned media from IL-10 deficient mice promoted SASP secretion and upregulated senescence genes in naïve lung fibroblasts, which was mitigated by rIL-10 treatment. Mechanistically, rIL-10 inhibited TGF-β-Smad2/3 and PTEN/PI3K/AKT/ERK pathways, thereby suppressing senescence and fibrosis-related proteins.
Conclusions: IL-10 deficiency in aged mice leads to accelerated cell senescence and exacerbated fibrosis, with IL-10KO-PLFs displaying increased SASP secretion. Recombinant IL-10 treatment effectively mitigates these effects, suggesting its potential as a therapeutic target for PF.
(© 2024. The Author(s).)
Databáze: MEDLINE
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