PMID- 37593979 OWN - NLM STAT- MEDLINE DCOM- 20230821 LR - 20231028 IS - 2001-3078 (Electronic) IS - 2001-3078 (Linking) VI - 12 IP - 8 DP - 2023 Aug TI - ApoE expression in macrophages communicates immunometabolic signaling that controls hyperlipidemia-driven hematopoiesis & inflammation via extracellular vesicles. PG - e12345 LID - 10.1002/jev2.12345 [doi] LID - e12345 AB - While apolipoprotein E (apoE) expression by myeloid cells is recognized to control inflammation, whether such benefits can be communicated via extracellular vesicles is not known. Through the study of extracellular vesicles produced by macrophages derived from the bone marrow of Wildtype (WT-BMDM-EV) and ApoE deficient (EKO-BMDM-EV) mice, we uncovered a critical role for apoE expression in regulating their cell signaling properties. WT-BMDM-EV communicated anti-inflammatory properties to recipient myeloid cells by increasing cellular levels of apoE and miR-146a-5p, that reduced NF-kappaB signalling. They also downregulated cellular levels of miR-142a-3p, resulting in increased levels of its target carnitine palmitoyl transferase 1A (CPT1A) which improved fatty acid oxidation (FAO) and oxidative phosphorylation (OxPHOS) in recipient cells. Such favorable metabolic polarization enhanced cell-surface MerTK levels and the phagocytic uptake of apoptotic cells. In contrast, EKO-BMDM-EV exerted opposite effects by reducing cellular levels of apoE and miR-146a-5p, which increased NF-kappaB-driven GLUT1-mediated glucose uptake, aerobic glycolysis, and oxidative stress. Furthermore, EKO-BMDM-EV increased cellular miR-142a-3p levels, which reduced CPT1A levels and impaired FAO and OxPHOS in recipient myeloid cells. When cultured with naive CD4(+) T lymphocytes, EKO-BMDM-EV drove their activation and proliferation, and fostered their transition to a Th1 phenotype. While infusions of WT-BMDM-EV into hyperlipidemic mice resolved inflammation, infusions of EKO-BMDM-EV increased hematopoiesis and drove inflammatory responses in myeloid cells and T lymphocytes. ApoE-dependent immunometabolic signaling by macrophage extracellular vesicles was dependent on transcriptional axes controlled by miR-146a-5p and miR-142a-3p that could be reproduced by infusing miR-146a mimics & miR-142a antagonists into hyperlipidemic apoE-deficient mice. Together, our findings unveil a novel property for apoE expression in macrophages that modulates the immunometabolic regulatory properties of their secreted extracellular vesicles. CI - (c) 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. FAU - Phu, Tuan Anh AU - Phu TA AD - Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, California, USA. AD - Northern California Institute for Research and Education, San Francisco, California, USA. FAU - Ng, Martin AU - Ng M AD - Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, California, USA. AD - Northern California Institute for Research and Education, San Francisco, California, USA. FAU - Vu, Ngan K AU - Vu NK AD - Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, California, USA. AD - Northern California Institute for Research and Education, San Francisco, California, USA. FAU - Gao, Alex S AU - Gao AS AD - Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, California, USA. AD - Northern California Institute for Research and Education, San Francisco, California, USA. FAU - Raffai, Robert L AU - Raffai RL AUID- ORCID: 0000-0002-5442-3055 AD - Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, California, USA. AD - Northern California Institute for Research and Education, San Francisco, California, USA. AD - Department of Surgery, Division of Endovascular and Vascular Surgery, University of California, San Francisco, California, USA. LA - eng GR - IK6 BX005692/BX/BLRD VA/United States GR - P30 DK063720/DK/NIDDK NIH HHS/United States GR - R01 HL133575/HL/NHLBI NIH HHS/United States GR - UG3 CA241703/CA/NCI NIH HHS/United States GR - I01 BX003928/BX/BLRD VA/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. PL - United States TA - J Extracell Vesicles JT - Journal of extracellular vesicles JID - 101610479 RN - 0 (NF-kappa B) RN - 0 (Apolipoproteins E) RN - 0 (MicroRNAs) SB - IM EIN - J Extracell Vesicles. 2023 Nov;12(11):e12375. PMID: 37885049 MH - Animals MH - Mice MH - *Extracellular Vesicles MH - NF-kappa B MH - *Hyperlipidemias MH - Signal Transduction MH - Macrophages MH - Inflammation MH - Apolipoproteins E/genetics MH - *MicroRNAs PMC - PMC10436255 OTO - NOTNLM OT - ApoE OT - extracellular vesicles OT - immunometabolism OT - inflammation OT - macrophage OT - microRNA OT - oxidative stress COIS- There is no conflict of interest in writing this manuscript. EDAT- 2023/08/18 12:42 MHDA- 2023/08/21 06:42 PMCR- 2023/08/18 CRDT- 2023/08/18 06:36 PHST- 2023/06/21 00:00 [revised] PHST- 2022/07/14 00:00 [received] PHST- 2023/06/22 00:00 [accepted] PHST- 2023/08/21 06:42 [medline] PHST- 2023/08/18 12:42 [pubmed] PHST- 2023/08/18 06:36 [entrez] PHST- 2023/08/18 00:00 [pmc-release] AID - JEV212345 [pii] AID - 10.1002/jev2.12345 [doi] PST - ppublish SO - J Extracell Vesicles. 2023 Aug;12(8):e12345. doi: 10.1002/jev2.12345.