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

Alla Malinina, Dustin Dikeman, Reyhan Westbrook, Michelle Moats, Sarah Gidner, Hataya Poonyagariyagorn, Jeremy Walston, Enid R. Neptune

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalAging Cell
DOIs
StateAccepted/In press - Jan 1 2020

Keywords

  • IL10
  • MMP12
  • alveolar epithelial cells
  • emphysema
  • lymphoid aggregates
  • macrophages

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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    Malinina, A., Dikeman, D., Westbrook, R., Moats, M., Gidner, S., Poonyagariyagorn, H., Walston, J., & Neptune, E. R. (Accepted/In press). IL10 deficiency promotes alveolar enlargement and lymphoid dysmorphogenesis in the aged murine lung. Aging Cell. https://doi.org/10.1111/acel.13130