According to a study published in Cell, a common transcriptional pathway might be used by macrophages to facilitate the clearance of both oxidatively modified lipoproteins and intracellular bacteria that have been phagocytosed. The nuclear liver X receptors LXR-α and LXR-β are known to facilitate the transcription of genes that promote cholesterol efflux from macrophages after scavenger-receptor-mediated uptake of oxidized lipids. Now, they are also shown to mediate innate immune responses to intracellular bacteria, and these responses promote macrophage survival and pathogen clearance.

Mice that are deficient in both LXR-α and LXR-β (LXR-αβ-deficient mice) were highly susceptible to infection with the Gram-positive intracellular bacterium Listeria monocytogenes, succumbing to infection earlier than wild-type controls and having higher bacterial burdens in the liver. Susceptibility was shown to be associated mainly with loss of LXR-α. Transplantation of wild-type bone marrow to LXR-αβ-deficient recipients completely reversed the susceptibility phenotype, showing that the defect occurs in bone-marrow-derived cells and not in hepatocytes, in which LXR proteins are also highly expressed.

The early susceptibility of LXR-αβ-deficient mice to L. monocytogenes indicated that the innate immune response might be affected. So, to identify LXR-regulated genes that are involved in innate immunity, the authors used transcriptional profiling to identify genes that were induced by both L. monocytogenes and LXR agonists, and were preferentially induced by LXR-α compared with LXR-β. The only gene that met these criteria was the gene encoding the anti-apoptotic protein SP-α, which is known to be selectively expressed by macrophages. Furthermore, they identified a putative site in the SP-α promoter for the binding of LXR proteins and their heterodimeric partner retinoid X receptor (RXR). LXR-α–RXR heterodimers bound this site with high affinity compared with LXR-β–RXR heterodimers.

So, SP-α can be directly induced by LXR-α, and the authors showed that, in turn, expression of mRNA encoding LXR-α (but not LXR-β) is strongly induced by bone-marrow-derived macrophages after exposure to L. monocytogenes. A similar response was observed for the Gram-negative intracellular bacterium Shigella flexneri, but not for Gram-positive and Gram-negative extracellular bacteria, indicating that induction of expression of LXR-α is a preferential response to intracellular bacteria. Induction of LXR-α was shown to be independent of the Toll-like receptor pathway but to involve intracellular NOD (nucleotide-binding oligomerization domain) proteins.

In keeping with the known anti-apoptotic effects of SP-α, macrophages from LXR-αβ-deficient mice infected with L. monocytogenes had an increased rate of apoptosis compared with wild-type macrophages. Forced expression of LXR-α by RAW264.7 macrophages, which express LXR-β but not LXR-α, led to the expression of SP-α and inhibited apoptosis when the cells were challenged with L. monocytogenes. Expression of LXR-α also decreased the number of viable intracellular bacteria. Because the induction of apoptosis by pathogens is a common strategy to evade the host immune response, the upregulation of SP-α by infected macrophages might be an important counter-defence to facilitate pathogen clearance.