Open AccessDifferential regulation of TREM2 and CSF1R in CNS macrophages in an SIV/macaque model of HIV CNS disease
Author(s) -
Audrey C. Knight,
Samuel A. Brill,
Clarisse V. Solis,
Morgan R. Richardson,
Megan E. McCarron,
Suzanne E. Queen,
Charles C. Bailey,
Joseph L. Mankowski
Publication year - 2020
Publication title -
journal of neurovirology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.868
H-Index - 85
eISSN - 1538-2443
pISSN - 1355-0284
DOI - 10.1007/s13365-020-00844-1
Subject(s) - macaque , trem2 , simian immunodeficiency virus , microglia , virology , human immunodeficiency virus (hiv) , central nervous system , macrophage , disease , biology , neuroscience , immunology , medicine , pathology , inflammation , in vitro , genetics
HIV-associated neuroinflammation is primarily driven by CNS macrophages including microglia. Regulation of these immune responses, however, remains to be characterized in detail. Using the SIV/macaque model of HIV, we evaluated CNS expression of triggering receptor expressed on myeloid cells 2 (TREM2) which is constitutively expressed by microglia and contributes to cell survival, proliferation, and differentiation. Loss-of-function mutations in TREM2 are recognized risk factors for neurodegenerative diseases including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Nasu-Hakola disease (NHD); recent reports have also indicated a role for TREM2 in HIV-associated neuroinflammation. Using in situ hybridization (ISH) and qRT-PCR, TREM2 mRNA levels were found to be significantly elevated in frontal cortex of macaques with SIV encephalitis compared with uninfected controls (P = 0.02). TREM2 protein levels were also elevated as measured by ELISA of frontal cortex tissue homogenates in these animals. Previously, we characterized the expression of CSF1R (colony-stimulating factor 1 receptor) in this model; the TREM2 and CSF1R promoters both contain a PU.1 binding site. While TREM2 and CSF1R mRNA levels in the frontal cortex were highly correlated (Spearman R = 0.79, P < 0.001), protein levels were not well correlated. In SIV-infected macaques released from ART to study viral rebound, neither TREM2 nor CSF1R mRNA increased with rebound viremia. However, CSF1R protein levels remained significantly elevated unlike TREM2 (P = 0.02). This differential expression suggests that TREM2 and CSF1R play unique, distinct roles in the pathogenesis of HIV CNS disease.