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

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 PPAR delta as relevant transcriptional regulators, while PPAR gamma did not substantially contribute to gene regulation. Mechanistically, lysosomal digestion and lysosomal acid lipase (LIPA) were required for PPAR and LXR activation, while PPAR delta activation also demanded an active lysosomal phospholipase A(2) (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 PPAR delta. These data provide mechanistic details on LXR and PPAR delta activation in efferocytotic human macrophages.

Automated summary

Efferocytosis is crucial for maintaining tissue homeostasis and involves activation of transcription factors such as PPAR and LXR. This study explored the transcriptional profile of macrophages following uptake of apoptotic cells, showing upregulation of PPAR and LXR pathways. The activation mechanisms of PPAR and LXR in efferocytotic human macrophages were elucidated, providing insights into their roles in metabolic and inflammatory responses.