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Different mechanisms of apolipoprotein E isoform‐dependent modulation of prostaglandin E 2 production and triggering receptor expressed on myeloid cells 2 ( TREM2 ) expression after innate immune activation of microglia
Author(s) -
Li Xianwu,
Montine Kathleen S.,
Keene C. Dirk,
Montine Thomas J.
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-262683
Subject(s) - trem2 , microglia , apolipoprotein e , innate immune system , receptor , endocrinology , biology , proinflammatory cytokine , microbiology and biotechnology , medicine , inflammation , chemistry , immunology , biochemistry , disease
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 ) ɛ4 carriers; inhibitors of prostaglandin (PG) synthesis show a partially protective effect on AD risk from APOE ɛ4; 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 ɛ4 inheritance modulates both the PGE 2 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‐Hght‐chain‐enhancer inhibitor blocked TR APOE4/4‐dependent effects on the PGE 2 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.—Li, X., Montine, K. S., Keene, C. D., Montine, T. J. Different mechanisms of apolipoprotein E isoform‐dependent modulation of prostaglandin E 2 production and triggering receptor expressed on myeloid cells 2 ( TREM2 ) expression after innate immune activation of microglia. FASEB J. 29, 1754‐1762 (2015). www.fasebj.org