HIV-1 Tat promotes astrocytic release of CCL2 through MMP/PAR-1 signaling.

TitleHIV-1 Tat promotes astrocytic release of CCL2 through MMP/PAR-1 signaling.
Publication TypeJournal Article
Year of Publication2019
AuthorsP Bozzelli, L, Yin, T, Avdoshina, V, Mocchetti, I, Conant, KE, Maguire-Zeiss, KA
Date Published2019 09
KeywordsAdult, Animals, Astrocytes, Cells, Cultured, Cerebral Cortex, Chemokine CCL2, Female, HIV-1, Humans, Male, Matrix Metalloproteinases, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Protein-Serine-Threonine Kinases, Signal Transduction, tat Gene Products, Human Immunodeficiency Virus

The HIV-1 protein Tat is continually released by HIV-infected cells despite effective combination antiretroviral therapies (cART). Tat promotes neurotoxicity through enhanced expression of proinflammatory molecules from resident and infiltrating immune cells. These molecules include matrix metalloproteinases (MMPs), which are pathologically elevated in HIV, and are known to drive central nervous system (CNS) injury in varied disease settings. A subset of MMPs can activate G-protein coupled protease-activated receptor 1 (PAR-1), a receptor that is highly expressed on astrocytes. Although PAR-1 expression is increased in HIV-associated neurocognitive disorder (HAND), its role in HAND pathogenesis remains understudied. Herein, we explored Tat's ability to induce expression of the PAR-1 agonists MMP-3 and MMP-13. We also investigated MMP/PAR-1-mediated release of CCL2, a chemokine that drives CNS entry of HIV infected monocytes and remains a significant correlate of cognitive dysfunction in the era of cART. Tat exposure significantly increased the expression of MMP-3 and MMP-13. These PAR-1 agonists both stimulated the release of astrocytic CCL2, and both genetic knock-out and pharmacological inhibition of PAR-1 reduced CCL2 release. Moreover, in HIV-infected post-mortem brain tissue, within-sample analyses revealed a correlation between levels of PAR-1-activating MMPs, PAR-1, and CCL2. Collectively, these findings identify MMP/PAR-1 signaling to be involved in the release of CCL2, which may underlie Tat-induced neuroinflammation.

Alternate JournalGlia
PubMed ID31124192
PubMed Central IDPMC6640102
Grant ListR01 NS083410 / NS / NINDS NIH HHS / United States
R01 NS079172 / NS / NINDS NIH HHS / United States
U24 MH100928 / MH / NIMH NIH HHS / United States
U24MH100931 / NH / NIH HHS / United States
R01 NS108810 / NS / NINDS NIH HHS / United States
U24MH100928 / NH / NIH HHS / United States
U24MH100925 / NH / NIH HHS / United States
T32 NS041218 / NS / NINDS NIH HHS / United States