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EphB2-mediated ephrin-B reverse signaling on microglia drives an antiviral but also inflammatory response in HIV

ABSTRACT: HIV Associated Neurocognitive Disorder (HAND) is a condition behaviorally characterized by cognitive and neurological impairments, and pathologically characterized by neuroinflammation and a loss of synaptic integrity and function. Although therapeutics exist to increase the lifespan of people living with HIV, they are not effective at preventing HIV induced neuronal damage and the prevalence of HAND remains virtually unchanged. We observed an increase in expression of ephrin-B/EphB in post-mortem CNS specimen of people who lived with HIV and brain pathology. Given the previously recognized impact of EphB2 on inflammation in the periphery, the functional role of EphB2-mediated ephrin-B reverse signaling on microglia was assessed. A a pro-inflammatory and antiviral mRNA expression profile was observed. The stimulation produced condirioned media, including secreted inflammatory factors, that were sufficient to induce non-cell contact-dependent neurotoxicity. Finally, knockdown of microglial ephrin-B1, EphB2 binding partner, resulted in a partial alleviation of the microglial pro-inflammatory signature and subsequent neurotoxicity. In this study, we show that elevated EphB2, and its reverse signaling through ephrin-B1 in microglia, can drive neuroinflammation and toxicity suggesting this pathway can mediate neurotoxicity in neuroHIV. Furthermore, we propose that this neuroinflammatory mechanism may play a role in promoting other neurodegenerative diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE260757 | GEO | 2024/06/01

REPOSITORIES: GEO

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Project description:Local cerebral hypoperfusion causes ischemic stroke while driving multiple cell-specific responses including inflammation, glutamate-NMDAR-mediated neurotoxicity, edema formation and angiogenesis. Despite the relevance of these pathophysiological mechanisms for disease progression and outcome, molecular determinants controlling the onset of these processes are only partially understood. In this context, our study intended to investigate the functional role of EphB2 – a receptor tyrosine kinase that is crucial for synapse function and binds to membrane-associated ephrin-B ligands. Cerebral ischemia was induced in EphB2-deficient mice by transient middle cerebral artery occlusion followed by different times (6, 12, 24 and 48 h) of reperfusion. Histological, neurofunctional and transcriptome analyses indicated an increase in EphB2 phosphorylation under these conditions and attenuated progression of stroke in EphB2-deficient mice. Moreover, while infiltration of microglia/macrophages and astrocytes into the peri-infarct region was not altered, expression of the pro-inflammatory mediators MCP-1 or IL-6 was decreased in these mice. In fact, in vitro analyses indicated that binding of EphB2 to astrocytic ephrin-B ligands stimulates NF-κB-mediated cytokine expression via the MAPK pathway. Further magnetic resonance imaging of the EphB2-deficient ischemic brain revealed a lower level of neuronal cytotoxic edema formation within 6 h upon onset of reperfusion. On the mechanistic level, absence of neuronal EphB2 decreased the mitochondrial Ca2+ load upon activation of NMDAR but not AMPAR. Moreover, activation of EphB2 by ephrin-B2 enhanced the NMDA-evoked excitotoxic neuronal cell death in vitro while neuron-specific loss of ephrin-B2 reduced the extent of cerebral tissue damage in the acute phase of ischemic stroke. Collectively, EphB2 may promote the immediate response to an ischemia-reperfusion event in the central nervous system by (i) pro-inflammatory activation of astrocytes via ephrin-B-dependent signalling and (ii) amplification of the NMDA-evoked neuronal excitotoxicity.

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EphB2-mediated ephrin-B reverse signaling on microglia drives an antiviral but also inflammatory response in HIV

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