Inhibition of LXR controls the polarization of human inflammatory macrophages through upregulation of MAFB

Abstract

Monocyte-derived macrophages contribute to pathogenesis in inflammatory diseases and their effector functions greatly depend on the prevailing extracellular milieu. Whereas M-CSF primes macrophages for acquisition of an anti-inflammatory profile, GM-CSF drives the generation of T cell-stimulatory and pro-inflammatory macrophages. Liver X Receptors (LXRα and LXRβ) are nuclear receptors that control cholesterol metabolism and regulate differentiation of tissue-resident macrophages. Macrophages from rheumatoid arthritis and other inflammatory pathologies exhibit an enriched LXR pathway, and recent reports have shown that LXR activation raises pro-inflammatory effects and impairs the acquisition of the anti-Inflammatory profile of M-CSF-dependent monocyte-derived macrophages (M-MØ). We now report that LXR inhibition prompts the acquisition of an anti-inflammatory gene and functional profile of macrophages generated within a pathological environment (synovial fluid from Rheumatoid Arthritis patients) as well as during the GM-CSF-dependent differentiation of human monocyte-derived macrophages (GM-MØ). Mechanistically, inhibition of LXR results in macrophages with higher expression of the v-Maf Avian Musculoaponeurotic Fibrosarcoma Oncogene Homolog B (MAFB) transcription factor, which governs the macrophage anti-inflammatory profile, as well as over-expression of MAFB-regulated genes. Indeed, gene silencing experiments on human macrophages evidenced that MAFB is required for the LXR inhibitor to enhance the anti-inflammatory nature of human macrophages. As a whole, our results demonstrate that LXR inhibition prompts the acquisition of an anti-inflammatory transcriptional and functional profile of human macrophages in a MAFB-dependent manner, and propose the use of LXR antagonists as potential therapeutic alternatives in macrophage re-programming strategies during inflammatory responses.

Single-cell analysis of a progressive Rosai–Dorfman disease affecting the cerebral parenchyma: a case report

“…Secreted phosphoprotein 1 (SPP1), a major noncollagenous protein of bone, is overexpressed in a wide range of cancers and is correlated with poor prognosis [ 4 ]. In this report, we found that SPP1+ histiocytes highly express genes associated with severe inflammation, such as WNT5A [ 7 ]; immunosuppression and phagocytosis, such as IL6 [ 8 ]; and ECM degradation, such as MMP12 [ 9 ]. These genes may thus confer the central role of SPP1+ histiocytes in the progression of this disease.…”

“…PyScenic analysis was then performed to investigate the upstream transcription factors (TFs) of the differentially expressed genes during the development of the histiocytes. The results showed that both C1Q+ and SPP1+ macrophages expressed mainly immunosuppressive-related TFs, such as MAFB [ 9 ] (Fig. 2 i).…”

Impact of Lipid Metabolism on Macrophage Polarization: Implications for Inflammation and Tumor Immunity

“…LXR activation has been shown to increase IFN-γ and M1 macrophage polarization, which may explain the reduction in tumors [29]. However, the effects of LXR activation or inhibition may be dependent on the LXR isoform, macrophage type, and associated tissues [30,31].…”

Cholesterol metabolism in rheumatic diseases

“…Кроме того, на первичной культуре CD4+ Т-клеток человека было показано, что в Т-клетках LXR регулировал метаболизм холестерина и гликосфинголипидов, а также активация LXR ослабляла провоспалительную функцию Т-клеток [40]. Тем не менее последние данные показывают, что ингибирование LXR вызывает дифференцировку макрофагов по противовоспалительному фенотипу, и предлагают использование антагонистов LXR в качестве потенциальных терапевтических стратегий лечения иммуновоспалительных заболеваний [41]. На рисунке представлены основные этапы метаболизма холестерина в организме.…”