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Different mechanisms of apolipoprotein E isoform-dependent modulation of prostaglandin E2 production and triggering receptor expressed on myeloid cells 2 (TREM2) expression after innate immune activation of microglia.
FASEB J. 2015 May; 29(5):1754-62.FJ

Abstract

Several lines of evidence support immune response in brain as a mechanism of injury in Alzheimer disease (AD). Moreover, immune activation is heightened in apolipoprotein E (APOE) ε4 carriers; inhibitors of prostaglandin (PG) synthesis show a partially protective effect on AD risk from APOE ε4; and genetic variants in triggering receptor expressed on myeloid cells 2 (TREM2) are a rare but potent risk for AD. We tested the hypothesis that APOE ε4 inheritance modulates both the PGE2 pathway and TREM2 expression using primary murine microglia from targeted replacement (TR) APOE3/3 and APOE4/4 mice. Microglial cyclooxygenase-2, microsomal PGE synthase, and PGE2 expression were increased 2- to 25-fold in both genotypes by TLR activators; however, this induction was significantly (P < 0.01) greater in TR APOE4/4 microglia with TLR3 and TLR4 activators. Microglial TREM2 expression was reduced approximately 85% by all TLR activators; this reduction was approximately one-third greater in microglia from TR APOE4/4 mice. Importantly, both receptor-associated protein and a nuclear factor κ-light-chain-enhancer inhibitor blocked TR APOE4/4-dependent effects on the PGE2 pathway but not on TREM2 expression. These data demonstrate complementary, but mechanistically distinct, regulation of pro- and anti-inflammatory mediators in TR APOE4/4 murine microglia that yields a more proinflammatory state than with TR APOE3/3.

Authors+Show Affiliations

Department of Pathology, University of Washington, Seattle, Washington, USA xli@uw.edu.Department of Pathology, University of Washington, Seattle, Washington, USA.Department of Pathology, University of Washington, Seattle, Washington, USA.Department of Pathology, University of Washington, Seattle, Washington, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25593125

Citation

Li, Xianwu, et al. "Different Mechanisms of Apolipoprotein E Isoform-dependent Modulation of Prostaglandin E2 Production and Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) Expression After Innate Immune Activation of Microglia." FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, vol. 29, no. 5, 2015, pp. 1754-62.
Li X, Montine KS, Keene CD, et al. Different mechanisms of apolipoprotein E isoform-dependent modulation of prostaglandin E2 production and triggering receptor expressed on myeloid cells 2 (TREM2) expression after innate immune activation of microglia. FASEB J. 2015;29(5):1754-62.
Li, X., Montine, K. S., Keene, C. D., & Montine, T. J. (2015). Different mechanisms of apolipoprotein E isoform-dependent modulation of prostaglandin E2 production and triggering receptor expressed on myeloid cells 2 (TREM2) expression after innate immune activation of microglia. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 29(5), 1754-62. https://doi.org/10.1096/fj.14-262683
Li X, et al. Different Mechanisms of Apolipoprotein E Isoform-dependent Modulation of Prostaglandin E2 Production and Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) Expression After Innate Immune Activation of Microglia. FASEB J. 2015;29(5):1754-62. PubMed PMID: 25593125.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Different mechanisms of apolipoprotein E isoform-dependent modulation of prostaglandin E2 production and triggering receptor expressed on myeloid cells 2 (TREM2) expression after innate immune activation of microglia. AU - Li,Xianwu, AU - Montine,Kathleen S, AU - Keene,C Dirk, AU - Montine,Thomas J, Y1 - 2015/01/15/ PY - 2014/08/07/received PY - 2014/12/15/accepted PY - 2015/1/17/entrez PY - 2015/1/17/pubmed PY - 2015/8/1/medline KW - Alzheimer disease KW - PGE2 KW - apolipoprotein E genotype KW - brain immunity KW - neuroinflammation SP - 1754 EP - 62 JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J. VL - 29 IS - 5 N2 - Several lines of evidence support immune response in brain as a mechanism of injury in Alzheimer disease (AD). Moreover, immune activation is heightened in apolipoprotein E (APOE) ε4 carriers; inhibitors of prostaglandin (PG) synthesis show a partially protective effect on AD risk from APOE ε4; and genetic variants in triggering receptor expressed on myeloid cells 2 (TREM2) are a rare but potent risk for AD. We tested the hypothesis that APOE ε4 inheritance modulates both the PGE2 pathway and TREM2 expression using primary murine microglia from targeted replacement (TR) APOE3/3 and APOE4/4 mice. Microglial cyclooxygenase-2, microsomal PGE synthase, and PGE2 expression were increased 2- to 25-fold in both genotypes by TLR activators; however, this induction was significantly (P < 0.01) greater in TR APOE4/4 microglia with TLR3 and TLR4 activators. Microglial TREM2 expression was reduced approximately 85% by all TLR activators; this reduction was approximately one-third greater in microglia from TR APOE4/4 mice. Importantly, both receptor-associated protein and a nuclear factor κ-light-chain-enhancer inhibitor blocked TR APOE4/4-dependent effects on the PGE2 pathway but not on TREM2 expression. These data demonstrate complementary, but mechanistically distinct, regulation of pro- and anti-inflammatory mediators in TR APOE4/4 murine microglia that yields a more proinflammatory state than with TR APOE3/3. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/25593125/Different_mechanisms_of_apolipoprotein_E_isoform_dependent_modulation_of_prostaglandin_E2_production_and_triggering_receptor_expressed_on_myeloid_cells_2__TREM2__expression_after_innate_immune_activation_of_microglia_ L2 - http://www.fasebj.org/doi/full/10.1096/fj.14-262683?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -