Abstract
In the retina, Müller glia is a dominant player of immune response. The HIV-1 transactivator viral protein (Tat) induces production of several neurotoxic cytokines in retinal cells. We show that HIV-1 clades Tat B and C act differentially on Müller glia, which is reflected in apoptosis, activation of cell death pathway components and pro-inflammatory cytokines. The harsher immune-mediated pathology of Tat B, as opposed to milder effects of Tat C, manifests at several signal transduction pathways, notably, MAPK, STAT, SOCS, the NFκB signalosome, and TTP. In activated cells, anandamide (AEA), acting as an immune-modulator, suppresses Tat B effect through MKP-1 but Tat C action via MEK-1. AEA lowers nuclear NF-κB and TAB2 for both variants while elevating IRAK1BP1 in activated Müller glia. Müller glia exposed to Tat shows enhanced PBMC attachment. Tat-induced increase in leukocyte adhesion to Müller cells can be mitigated by AEA, involving both CB receptors. This study identifies multiple signalling components that drive immune-mediated pathology and contribute to disease severity in HIV clades. We show that the protective effects of AEA occur at various stages in cytokine generation and are clade-dependant.
Highlights
We report that (1) Tat variants act to produce cytokines through different components of the MAPK, STAT and Suppressor of Cytokine Signalling (SOCS) pathway, (2) N-arachidonoylethanolamide (AEA) treatment, which promote anti-inflammatory milieu in cells exposed to either Tat variants, mediate this response through differential action on these pathways, and (3) monocyte adhesion can be diminished on exposure to AEA for both clades but through changes in expression of Mitogen-activated protein kinase kinase (MEK)-1 for Tat C and Mitogen-activated protein kinase phosphatase-1 (MKP-1) for Tat B
In this study we show that the disparity in innate immune response by Tat B and Tat C can be explained by differential effect on signal transduction pathways involved in cytokine production
We report the novel observation that the ability of AEA to create a pro-survival milieu in Tat-activated Müller glia is differentially regulated in clades B and C
Summary
We investigate differences in innate immune response and ability to attract monocytes on exposure to clade B and clade C HIV-1 Tat in retinal Müller glia. Endocannabinoids are being increasingly explored as immune-modulators They suppress inflammation by inhibiting release of inflammatory mediators. Little is known about how engagement of the cannabinoid receptors affect the activated state of the Müller glia which participate in blood-retinal barrier functions. We report that (1) Tat variants act to produce cytokines through different components of the MAPK, STAT and SOCS pathway, (2) N-arachidonoylethanolamide (AEA) treatment, which promote anti-inflammatory milieu in cells exposed to either Tat variants, mediate this response through differential action on these pathways, and (3) monocyte adhesion can be diminished on exposure to AEA for both clades but through changes in expression of MEK-1 for Tat C and Mitogen-activated protein kinase phosphatase-1 (MKP-1) for Tat B. Our work shows that in the retina, regulation of Müller glial innate immune response, ability to attach leukocytes and the machinery involved in cytokine production is clade specific
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