Immunology Cholesterol Signals

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

An appropriate immune response to an invading organism requires coordination between innate immune cells, such as macrophages, which are among the first responders, and adaptive immune cells, such as T and B cells, which respectively produce cytokines and antibodies against the pathogen. In mucosal tissues, immunoglobulin A (IgA) produced by B cells suppresses inflammation and helps to clear microorganisms. Bauman et al. investigated the role of factors secreted by macrophages in response to stimulation of Toll-like receptors (TLRs) that might modulate the responses of B cells. Stimulation of mouse macrophages with the TLR4 ligand KDO increased the abundance of cholesterol 25-hydroxylase (CH25H) mRNA and protein and caused the secretion of 25-hydroxycholesterol. Other TLR agonists had the same effect. The response to KDO depended on mitogen-activated protein kinases and the transcription factor nuclear factor B. Administration of KDO to mice induced the expression of Ch25h in many tissues that have resident populations of macrophages, including the liver and the lung. Ch25h^–/– mice had more IgA in serum, lungs, and mucosal sites than did wild-type mice, whereas mice deficient in the enzyme CYP7B1, which metabolizes 25-hydroxycholesterol, had the lowest amounts of IgA. Loss of Ch25h had no effect on any of the lymphocyte populations or cytokines known to affect B cell function in vivo, but 25-hydroxycholesterol inhibited the synthesis and secretion of IgA by mouse splenic B cells in vitro. 25-Hydroxycholesterol inhibited expression of the gene encoding activation-induced cytidine deaminase, which is required for the chromosomal rearrangements necessary for the generation of IgA. Together, these data suggest a mechanism whereby microorganisms might trigger a TLR-dependent response in macrophages to inhibit part of the adaptive immune response to their presence.

D. R. Bauman, A. D. Bitmansour, J. G. McDonald, B. M. Thompson, G. Liang, D. W. Russell, 25-Hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A production. Proc. Natl. Acad. Sci. U.S.A. 106, 16764–16769 (2009). [Abstract] [Full Text]