Lipocalin-2 mediates HIV-1 induced neuronal injury and behavioral deficits by overriding CCR5-dependent protection.

Brain, Behavior, and Immunity
Daniel Ojeda-JuárezMarcus Kaul

Abstract

People living with HIV (PLWH) continue to develop HIV-associated neurocognitive disorders despite combination anti-retroviral therapy. Lipocalin-2 (LCN2) is an acute phase protein that has been implicated in neurodegeneration and is upregulated in a transgenic mouse model of HIV-associated brain injury. Here we show that LCN2 is significantly upregulated in neocortex of a subset of HIV-infected individuals with brain pathology and correlates with viral load in CSF and pro-viral DNA in neocortex. However, the question if LCN2 contributes to HIV-associated neurotoxicity or is part of a protective host response required further investigation. We found that the knockout of LCN2 in transgenic mice expressing HIVgp120 in the brain (HIVgp120tg) abrogates behavioral impairment, ameliorates neuronal damage, and reduces microglial activation in association with an increase of the neuroprotective CCR5 ligand CCL4. In vitro experiments show that LCN2 neurotoxicity also depends on microglia and p38 MAPK activity. Genetic ablation of CCR5 in LCN2-deficient HIVgp120tg mice restores neuropathology, suggesting that LCN2 overrides neuroprotection mediated by CCR5 and its chemokine ligands. RNA expression of 168 genes involved in neurotransmissio...Continue Reading

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Citations

Jul 31, 2020·Journal of Neuroinflammation·Hina SinghMarcus Kaul
Jul 11, 2021·Brain, Behavior, and Immunity·Brennan OlsonDaniel L Marks
Jul 30, 2021·Ageing Research Reviews·Doortje W DekensPetrus J W Naudé
Sep 2, 2021·American Journal of Physiology. Lung Cellular and Molecular Physiology·Stephanie GuardadoTara M Nordgren

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