Liver X Receptors in Bacterial Clearance

Abstract

Liver X receptors (LXRs) are well known for acting as heterodimers with retinoid X receptors (RXRs) to regulate the expression of genes involved in lipid metabolism. Joseph et al . expand the role of the LXRα isoform to include regulation of susceptibility to bacterial infection. Mice lacking either both the α and β isoforms or just the α isoform of LXR showed more rapid mortality to Listeria monocytogenes infection and increased bacterial burden. Macrophages deficient in LXR were also more susceptible to apoptosis in response to L. monocytogenes infection. Gene expression analysis identified the gene encoding SPα (also known as API6 for apoptosis inhibitor 6, which is a member of the scavenger receptor cystine-rich repeat family) as the single gene induced by L. monocytogenes infection and exposure to an LXR agonist and differentially expressed by LXR α —/— and LXR β —/— mice. The mRNA for LXR α was increased in bone marrow-derived macrophages infected with Shigella flexneri or L. monocytogenes and to a lesser extent in cells infected with Escherichia coli or Staphylococcus aureus . LXR α mRNA was also increased in response to exposure to agonist for the NOD2 (nucleotide binding oligomerization domain) protein, but did not require the TLR (Toll-like receptor) pathway. Forced expression of either SPα or LXRα in RAW264.7 macrophages inhibited apoptosis upon exposure to L. monocytogenes . These results expand the role for LXRs beyond lipid metabolism into the realm of innate immunity and open questions as to whether there are more connections between the lipid-sensing nuclear receptors, immunity, and inflammation (see Barish and Evans). S. B. Joseph, M. N. Bradley, A. Castrillo, K. W. Bruhn, P. A. Mak, L. Pei, J. Hogenesch, R. M. O'Connell, G. Cheng, E. Saez, J. F. Miller, P. Tontonoz, LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell 119 , 299-309 (2004). [Online Journal] G. D. Barish, R. M. Evans, A nuclear strike against Listeria : The evolving life of LXR. Cell 119 , 149-151 (2004). [Online Journal]