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

Ana Carolina Mota,Bernhard Brüne,Andreas Weigert,Dmitry Namgaladze,Ryan G Snodgrass,Monica Dominguez

doi:10.3389/fimmu.2021.637778

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.

Highlights

Macrophage (Mj) engulfment of apoptotic cells (AC), a process known as efferocytosis, promotes resolution of inflammation and tissue repair, while restricting autoreactive immune responses [1]
We analyzed the mRNA expression of classical liver X receptors (LXR) target genes, i.e., ABCA1 and ABCG1 as well as PPARd/g targets pyruvate dehydrogenase kinase 4 (PDK4) and carnitine palmitoyltransferase 1A (CPT1A) (Figure 1D)
Our data show that LXRs, peroxisome proliferator-activated receptors (PPAR) and sterol regulatory element-binding proteins (SREBP) are the main transcriptional regulators of lipid metabolism in efferocytotic human Mj

Summary

Introduction

Macrophage (Mj) engulfment of apoptotic cells (AC), a process known as efferocytosis, promotes resolution of inflammation and tissue repair, while restricting autoreactive immune responses [1]. Efferocytosis is a coordinated sequence of events, which starts with recognition of AC and culminates in their phagocytosis, followed by phagolysosomal processing [2]. Effective clearance of AC is essential for maintaining tissue homeostasis. More recent studies pointed to its importance in resolution of inflammation, immune tolerance, and cancer development [3]. A better understanding of efferocytosis is key to comprehend major pathophysiological processes.

Methods

Results

Conclusion