Lysosome-Dependent LXR and PPARδ Activation Upon Efferocytosis in Human Macrophages

Abstract

Efferocytosis is critical for tissue homeostasis, as its deregulation is associated with several autoimmune pathologies. While engulfing apoptotic cells, phagocytes activate transcription factors, such as peroxisome proliferator-activated receptors (PPAR) or liver X receptors (LXR) that orchestrate metabolic, phagocytic, and inflammatory responses towards the ingested material. Coordination of these transcription factors in efferocytotic human macrophages is not fully understood. In this study, we evaluated the transcriptional profile of macrophages following the uptake of apoptotic Jurkat T cells using RNA-seq analysis. Results indicated upregulation of PPAR and LXR pathways but downregulation of sterol regulatory element-binding proteins (SREBP) target genes. Pharmacological inhibition and RNA interference pointed to LXR and PPARδ as relevant transcriptional regulators, while PPARγ did not substantially contribute to gene regulation. Mechanistically, lysosomal digestion and lysosomal acid lipase (LIPA) were required for PPAR and LXR activation, while PPARδ activation also demanded an active lysosomal phospholipase A2 (PLA2G15). Pharmacological interference with LXR signaling attenuated ABCA1-dependent cholesterol efflux from efferocytotic macrophages, but suppression of inflammatory responses following efferocytosis occurred independently of LXR and PPARδ. These data provide mechanistic details on LXR and PPARδ activation in efferocytotic human macrophages.

Alveolar macrophage metabolic programming via a C-type lectin receptor protects against lipo-toxicity and cell death

“…The engulfed lipids by AM during routine surfactant turnover and clearance of apoptotic debris in the lung, generate ligands for nuclear receptors that modulate lipid metabolism and phagolysosome processing 56 . Given the observed changes in both lipid uptake and expression of transcriptional activators of lipid metabolism in Nkrp1b − / − AM, we assessed if NKR-P1B altered phagolysosome formation.…”

The resolution of phagosomes

“…Intracellular cholesterol levels increase significantly with phagocytosis and degradation of apoptotic corpses 238 . In physiologic states, these sterols are metabolized to oxysterols 24 which activate transcription factors such as PPARγ and liver X receptor (LXR) 239 . LXR induces expression of the plasma membrane lipid transporters Abca1 and Abcg1 which regulate cholesterol efflux 240 .…”

Mechanisms of efferocytosis in determining inflammation resolution: Therapeutic potential and the association with cardiovascular disease

“…Previous studies suggested that the nuclear hormone receptor superfamilies (including liver X receptors (LXR), retinoid X receptors and peroxisome proliferator activated receptors (PPAR)) that regulate the genes involved in lipid metabolism and transport played a critical role in mediating the association (Roszer, 2017; Snodgrass et al, 2021). For example, the uptake of apoptotic Jurkat T cells by macrophages activates the LXR and PPAR pathways and down‐regulates the expression of sterol regulatory element‐binding protein (SREBP) target genes (Mota et al, 2021). Macrophages deficient in LXRs are unable to clear apoptotic thymocytes, but LXR deficiency in macrophages does not affect their processes of recognition and engulfment (A‐Gonzalez et al, 2009).…”

“…For example, the uptake of apoptotic Jurkat T cells by macrophages activates the LXR and PPAR pathways and down-regulates the expression of sterol regulatory element-binding protein (SREBP) target genes (Mota et al, 2021). Macrophages deficient in LXRs are unable to clear apoptotic thymocytes, but LXR deficiency in macrophages does not affect their processes of recognition and engulfment (A-Gonzalez et al, 2009).…”