Background/Purpose: LXRα is an oxysterol-regulated transcription factor that plays a key role in reverse cholesterol transport by inducing the expression of ATP binding cassette A1 (ABCA1) and other genes. LXRα also promotes macrophage (Mϕ) polarization away from proinflammatory (classically activated, M1) toward alternatively activated (M2) Mϕ. M1 Mϕ are metabolically dependent on glycolysis, whereas M2 Mϕ require oxidative metabolism. Hypoxia-inducible factor 1-α (HIF1α), a key regulator of glycolysis, promotes M1 Mϕ polarization. We have shown that Mϕ depletion prevents diffuse alveolar hemorrhage (DAH) in mice with pristane-induced lupus. The present study explored the mechanisms involved.

Methods: Murine Mϕ subsets were phenotyped by flow cytometry and the cell subsets were flow-sorted. Gene expression in SLE patients and mice with pristane-lupus was determined using RNA-Seq and real-time PCR. Cell metabolism was evaluated by extracellular flux analysis (Seahorse assay). Pristane-treated C57BL/6 mice received daily injections of the synthetic LXR agonist T0901317 (or vehicle) for 14-d after which we assessed DAH.

Results: Peritoneal Mϕ from pristane-treated mice had an M1 phenotype with high CD274, Ly6C, CD86, and TNFa expression and low CD273, Ym1, and IL-10 vs. mice treated with mineral oil (MO), a control inflammatory oil that does not cause lupus. MO treatment induced the opposite pattern from pristane, consistent with an M2 phenotype. Glycolytic metabolism (extracellular acidification rate, ECAR) was higher in pristane-treated mice (M1-like) whereas oxidative metabolism (oxygen consumption rate, OCR) was higher in MO-treated mice (M2-like). HIF1α and the HIF-regulated gene phosphofructokinase (PFKL) were higher in pristane-treated mice whereas LXRα and the LXR-regulated gene ABCA1 were higher in MO-treated mice. Similarly, SLE patients’ monocytes exhibited low LXRα/ABCA1 and high HIF1α/PFKL expression vs. healthy controls consistent with M1 polarization. T0901317 inhibited type I interferon and increased ABCA1 in vitro in both SLE patients’ monocytes and in mice. In pristane-lupus, T0901317 re-polarized Mϕ to M2, increased Mϕ OCR, and decreased TNFα. It also completely abolished autoimmune lung disease (DAH).

Conclusion: Mϕ may play a more important role in SLE than previously recognized. Murine and human SLE both are associated with low LXR activity in Mϕ and monocytes. Our data suggest that high LXRa activity is a marker for the generation of M2 Mϕ, which mediate the resolution of chronic inflammation, while protecting from end-organ disease in lupus. LXR agonist therapy prevents DAH in mice and raises ABCA1 expression on patients’ monocytes in vitro, suggesting a possible therapeutic role in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/liver-x-receptor-%ce%b1-lxr%ce%b1-modulates-macrophage-phenotype-and-disease-activity-in-sle/