TY  - JOUR
A1  - Mota, Ana Carolina
A1  - Dominguez, Monica
A1  - Weigert, Andreas
A1  - Snodgrass, Ryan G.
A1  - Namgaladze, Dmitry
A1  - Brüne, Bernhard
T1  - Lysosome-Dependent LXR and PPARδ Activation Upon Efferocytosis in Human Macrophages
T2  - Frontiers in immunology
N2  - 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.
KW  - macrophages
KW  - efferocytosis
KW  - apoptosis
KW  - peroxisome proliferator-activated receptor
KW  - liver X receptor
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/61307
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-613072
SN  - 1664-3224
VL  - 12
IS  - art. 637778
SP  - 1
EP  - 10
PB  - Frontiers Media
CY  - Lausanne
ER  -