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  • INCB3344 australia Because HIV does not infect

    2022-05-13

    Because HIV does not infect neurons, the neurotoxicity in HAND is thought to result from the neuroinflammation evoked by the release of viral proteins and cytokines from infected microglia and macrophages (Ellis et al., 2007; Saylor et al., 2016). Viral tropism is determined by gp120 binding to CD4 and a chemokine co-receptor. The IIIB strain of gp120 used in this study binds to CXCR4 (Islam et al., 2013; Moore et al., 1997), consistent with inhibition of gp120-evoked effects by a CXCR4 receptor antagonist. Recombinant gp120IIIB has previously been shown to induce release of inflammatory cytokines, including IL-1β, from human monocytes (Clouse et al., 1991). CCR5 tropic gp120s induce release of IL-1β from microglia (Ashraf et al., 2014; Walsh et al., 2014). Thus, CCR5-preferring strains of gp120 would also be predicted to upregulate α5-containing GABAARs. Furthermore, neuronal injury resulting from INCB3344 australia of gp120IIIB is prevented in CCR5 knockout mice, suggesting CCR5 could also participate in the inflammatory response evoked by CXCR4-preferring strains of HIV (Maung et al., 2014). The effects observed were likely caused by CXCR4-mediated activation on microglia and subsequent IL-1β release. Removal of microglia using LME INCB3344 australia completely blocked the gp120-induced increase in tonic inhibition indicating microglia are essential for gp120-induced changes in GABAR signaling. Astrocytes have also been shown to play a significant role in gp120-induced toxicity (Bezzi et al., 2001) and we cannot rule out the possibility that they contributed to the increase in tonic inhibitory current. However, the signaling pathway proposed here (Fig. 6), in which microglia release of IL-1β that acts on neurons, is the most parsimonious pathway consistent with the results of this study. This model is consistent with prior studies from our laboratory and others showing that the highly potent (picomolar) effects that result from prolonged exposure to gp120 are indirect (Kim et al., 2011; Meucci and Miller, 1996; Viviani et al., 2006; Yang et al., 2013), whereas higher concentrations will elicit direct actions on neurons (Hesselgesser et al., 1998; Teodorof et al., 2014; Wenzel et al., 2017). IL-1β alone increased tonic inhibition, as previously reported (Wang et al., 2012), effectively mimicking the actions of gp120. Neurons express IL-1 receptors (Vezzani et al., 2011) and upregulation of tonic inhibition was blocked selectively by expression of a dominant negative form of p38 in neurons, suggesting that key steps in the downstream regulatory pathway are located within neurons (Fig. 6). However, we cannot exclude contributions from IL-1 receptors and p38 signaling in other cells types such as astrocytes (Ravizza and Vezzani, 2006) and microglia (Medders et al., 2010). P38 signaling in both microglia and neurons is necessary for gp120-induced cell death (Medders et al., 2010), and p38 is required for microglial production of inflammatory cytokines such as IL-1β (Schieven, 2005). We show here that activation of p38 MAPK in neurons is required to upregulate α5-containing GABAARs, however, our study does not address whether p38 in other cell types also contributed to the response. The gp120-induced increase in tonic inhibition was observed within 4 h and persisted during a 24 h exposure. This IL-1β-mediated increase in tonic current did not require protein synthesis and may be an early response to inflammation. It required activation of p38 MAPK as indicated by both pharmacological and dominant negative approaches. P38 is a known downstream effector of IL-1Rs although, how p38 regulates GABAARs is not clear. Immunocytochemistry experiments indicated that treatment with gp120 increased surface expression of α5 GABAAR subunits. Because inhibition of protein synthesis did not block the gp120-induced increase in tonic inhibition, p38 must alter the trafficking of α5-containing GABAARs. This finding is consistent with a previous study that found exposure to IL-1β increased trafficking of α5-containing GABAARs to the cell surface (Wang et al., 2012). Protein kinases such as CamKii and PKC increase trafficking of GABAARs to the cell surface by phosphorylating the β3 and α4 subunits, respectively (Abramian et al., 2014; Saliba et al., 2012). However, p38 mediated phosphorylation of GABAAR subunits has not been reported so whether p38 acts directly or via an intermediary step is not clear.