25-Hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A production
Open accessAbstract
25-Hydroxycholesterol is produced in mammalian tissues. The function of this oxysterol is unknown. Here we describe a central role for 25-hydroxycholesterol in regulating the immune system. In initial experiments, we found that stimulation of macrophage Toll-like receptors (TLR) induced expression of cholesterol 25-hydroxylase and the synthesis of 25-hydroxycholesterol. Treatment of naïve B cells with nanomolar concentrations of 25-hydroxycholesterol suppressed IL-2-mediated stimulation of B cell proliferation, repressed activation-induced cytidine deaminase (AID) expression, and blocked class switch recombination, leading to markedly decreased IgA production. Consistent with these findings, deletion of the mouse cholesterol 25-hydroxylase gene caused an increase in serum IgA. Conversely, inactivation of the CYP7B1 oxysterol 7α-hydroxylase, which degrades 25-hydroxycholesterol, decreased serum IgA. The suppression of IgA class switching in B cells by a macrophage-derived sterol in response to TLR activation provides a mechanism for local and systemic negative regulation of the adaptive immune response by the innate immune system.
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Ch25h, the enzyme that hydroxylates cholesterol to 25HC, is markedly upregulated by toll-like receptor activation of macrophages.
“Ch25h, the enzyme that hydroxylates cholesterol to 25-hydroxycholesterol (25HC) (9) is markedly upregulated by toll-like receptor activation of macrophages (10,11).”
From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [10]
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- Authors
- Bauman, D. R., Bitmansour, A. D., McDonald, J. G., Thompson, B. M., Liang, G., & Russell, D. W.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Department of Molecular Genetics and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-09-29
- Volume
- 106
- Issue
- 39
- Pages
- 16764-16769
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2757821
- OpenAlex
- W2038363528
- Cited by
- 329
- References
- 34
- Citations by year
- 2026: 15 · 2025: 10 · 2024: 19 · 2023: 26 · 2022: 16 · 2021: 21 · 2020: 30 · 2019: 28 · 2018: 27 · 2017: 19 · 2016: 21 · 2015: 13 · 2014: 19 · 2013: 18 · 2012: 21
- FWCI
- 6.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Welch Foundation (I-0971)
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL 20848)
- National Institute of General Medical Sciences (U54GM069338, GM 069338)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 07745, T32DK007745)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- 25-hydroxycholesterol, oxysterols, macrophages, Toll-like receptor activation, immunoglobulin A, class switch recombination, activation-induced cytidine deaminase, B cell proliferation, cholesterol 25-hydroxylase, CYP7B1, negative regulation of immune response
- MeSH terms
- Animals, B-Lymphocytes, Hydroxycholesterols, Immunoglobulin A, Macrophages, Mice, Transgenic, Steroid Hydroxylases, Cytokines, Toll-Like Receptors, Mice
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