Heightened cholesterol 25-hydroxylase expression in aged lung during Streptococcus pneumoniae
David G Thomas1,2, Jianjun Yang1, Soo Jung Cho1,2
1Department of Medicine, Pulmonary and Critical Care, Weill Cornell Medicine, New York, NY, United States.
Introduction:
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.
Methods:
To observe the impact of aging on Ch25h expression in AM during infection, in vitro and in vivo murine models of S. pneumoniae were used.
Results:
At baseline and in response to infection, cholesterol metabolism significantly altered in aged AM, which corresponded with increased lipid droplet formation. In vitro, treatment of aged macrophages with Ch25 h-specific siRNA improved S. pneumoniae clearance and enhanced phagocytic receptor expression. In vivo siRNA targeting significantly reduced Ch25h expression in aged lungs and improved clinical parameters during S. pneumoniae infection. Reduction of Ch25h was associated with changes in phagocytosis and antibacterial signaling, correlated with changes in cholesterol metabolism, and increased S. pneumoniae clearance.
Discussion:
The results of our current study demonstrate that Ch25h plays an essential role in modulating aged AM responses to S. pneumoniae.
Insights
Cholesterol 25-hydroxylase (Ch25h) impacts aged alveolar macrophages during Streptococcus pneumoniae infection. Reducing Ch25h improves bacterial clearance and immune responses in aging lungs.
Area of Science:
- Immunology
- Cell Biology
- Aging Research
Background:
- Alveolar macrophages (AM) are crucial for lung immunity against Streptococcus pneumoniae.
- Altered lipid metabolism in AM can lead to inflammation and impaired function.
- Aging affects immune cell function, increasing susceptibility to infections.
Purpose of the Study:
- To investigate the role of cholesterol 25-hydroxylase (Ch25h) in aged AM during S. pneumoniae infection.
- To determine if modulating Ch25h affects AM responses and bacterial clearance in aging lungs.
Main Methods:
- Utilized in vitro and in vivo murine models of S. pneumoniae infection.
- Employed Ch25h-specific siRNA to reduce enzyme expression in aged macrophages and lungs.
- Assessed AM cholesterol metabolism, lipid droplet formation, phagocytic receptor expression, and bacterial clearance.
Main Results:
- Aging altered cholesterol metabolism and increased lipid droplets in AM.
- Ch25h inhibition in vitro enhanced S. pneumoniae clearance and phagocytic receptor expression.
- In vivo Ch25h reduction improved clinical outcomes and bacterial clearance in aged mice.
Conclusions:
- Cholesterol 25-hydroxylase (Ch25h) is a key regulator of aged AM function during S. pneumoniae infection.
- Targeting Ch25h represents a potential therapeutic strategy to enhance immune responses in aging lungs.
