IL10 deficiency promotes alveolar enlargement and lymphoid dysmorphogenesis in the aged murine lung

Abstract

The connection between aging‐related immune dysfunction and the lung manifestations of aging is poorly understood. A detailed characterization of the aging IL10‐deficient murine lung, a model of accelerated aging and frailty, reconciles features of both immunosenescence and lung aging in a coherent model. Airspace enlargement developed in the middle‐aged (12 months old) and aged (20–22 months old) IL10‐deficient lung punctuated by an expansion of macrophages and alveolar cell apoptosis. Compared to wild‐type (WT) controls, the IL10‐deficient lungs from young (4‐month‐old) mice showed increased oxidative stress which was enhanced in both genotypes by aging. Active caspase 3 staining was increased in the alveolar epithelial cells of aged WT and mutant lungs but was greater in the IL10‐deficient milieu. Lung macrophages were increased in the aged IL10‐deficient lungs with exuberant expression of MMP12. IL10 treatment of naïve and M2‐polarized bone marrow‐derived WT macrophages reduced MMP12 expression. Conditioned media studies demonstrated the secretome of aged mutant macrophages harbors reduced AECII prosurvival factors, specifically keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF), promotes cell death, and reduces survival of primary alveolar epithelial cells. Compared to WT controls, aged IL10‐deficient mice have increased parenchymal lymphoid collections comprised of a reduced number of apoptotic cells and B cells. We establish that IL10 is a key modulator of airspace homeostasis and lymphoid morphogenesis in the aging lung enabling macrophage‐mediated alveolar epithelial cell survival and B‐cell survival within tertiary lymphoid structures.

IL-10 and class 1 histone deacetylases act synergistically and independently on the secretion of proinflammatory mediators in alveolar macrophages

“…Previous studies have demonstrated that AM isolated from healthy nonsmoking human volunteers activate the expression of IL-10 upon stimulation with LPS [ 62 ]. Additionally, loss of IL-10 has been attributed to significant morphological functional changes in aged mice [ 63 ]. This indicates that IL-10 is key mediator of IL-10 homeostasis in the murine lung with either low level constitutive or intermittent expression.…”

Cucurbitacin I induces apoptosis in ovarian cancer cells through oxidative stress and the p190B‑Rac1 signaling axis

“…as shown in fig. 1, a noteworthy phenomenon was found, after cucurbitacin i administration, some of the shrunk cells that had attached to the culture dish still had cell viability and did not apoptosis is a form of programmed cell death that brings about the orderly and efficient removal of damaged cells, such as those resulting from dna damage or during development (25,26). The mechanism of apoptosis is very complex and numerous signaling pathways are involved in this process.…”

Native lamin A/C proteomes and novel partners from heart and skeletal muscle in a mouse chronic inflammation model of human frailty

“…Death was verified by observed cessation of breathing and heartbeat. Tissues were harvested, weighed, flash-frozen in liquid nitrogen and stored at −80°C as described ( Sikka et al, 2013 ; Malinina et al, 2020 ). All protocols were approved by the Johns Hopkins University Institutional Animal Care and Use Committee, and all experiments performed accordingly.…”

“…Because clinical frailty also strongly correlates with chronic inflammation, it is studied in a C57Bl/6 mouse model genetically deficient for the anti-inflammatory cytokine, Interleukin-10 (IL-10 B6.129P2- IL 10 tm/tm /J mice; Walston et al, 2008 ). These IL10 tm/tm (henceforth ‘IL10-KO’) mice experience lifelong chronic inflammation and exhibit multiple phenotypes consistent with human frailty including increased expression of NF-kB-dependent inflammatory mediators (e.g., IL-1β, TNFα, IFγ, IL-6, chemokine ligand-1; Walston et al, 2008 ; Ma et al, 2021 ) as well as age-associated reductions in strength, altered skeletal muscle gene expression, altered insulin signaling (high IGF-1), impaired mitochondrial degradation, high blood pressure, vascular stiffness, reduced fat, endothelial dysfunction, dysregulated tyrosine degradation and higher mortality ( Sikka et al, 2013 ; Westbrook et al, 2017 ; Lewsey et al, 2020 ; Malinina et al, 2020 ; Westbrook et al, 2020 ). Though primarily a model for chronic inflammation, IL10-KO mice are valuable for many purposes including the study of frailty.…”