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ORIGINAL RESEARCH article

Front. Aging
Sec. Molecular Mechanisms of Aging
Volume 5 - 2024 | doi: 10.3389/fragi.2024.1480886

Heightened Cholesterol 25-Hydroxylase Expression in Aged Lung during Streptococcus pneumoniae

Provisionally accepted
David G Thomas David G Thomas 1,2Jianjun Yang Jianjun Yang 1,2Soo Jung Cho Soo Jung Cho 1,2Heather W Stout-Delgado Heather W Stout-Delgado 1,2*
  • 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, United States
  • 2 Weill Cornell Medicine, Cornell University, New York, New York, United States

The final, formatted version of the article will be published soon.

    Alveolar macrophages (AM) are critical effectors of the immune response and are essential for host responses to Streptococcus pneumoniae. Changes in lipid metabolism in AM can alter cellular function and biology. Impaired metabolism can contribute to excessive lipid accumulation and pro-inflammatory signaling. Our current study was designed to examine the role of cholesterol 25-hydroxylase (Ch25h), a redox enzyme that catalyzes the oxidation of cholesterol to 25-hydroxycholesterol (25-HC), in modulating AM responses in the aged lung during S. pneumoniae infection Using in vitro and in vivo murine models of S. pneumoniae, we observed an age-associated increase in Ch25h expression in aged AM during infection At baseline, and in response to infection, there was a significant alteration in cholesterol metabolism in aged AM that corresponded with increased lipid droplet forma ion In vitro treatment of aged macrophages with Ch25h specific siRNA improved S. pneumoniae clearance and enhanced phagocytic receptor expression In vivo siRNA targeting significantly reduced Ch25h expression in aged lung and improved clinical parameters during S. pneumoniae infection. Reduction of Ch25h was associated with changes in phagocytosis and antibacterial signaling and was correlated with changes in cholesterol metabolism and increased S. pneumoniae clearance. Taken together, the results of our current study demonstrate an essential role for Ch25h in modulating aged AM responses to S. pneumoniae.

    Keywords: Lipid Metabolism, Streptococcus pneumoniae, Aging, Cholesterol, CH25H, macrophage

    Received: 14 Aug 2024; Accepted: 13 Nov 2024.

    Copyright: © 2024 Thomas, Yang, Cho and Stout-Delgado. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Heather W Stout-Delgado, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, United States

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