Connexin 43 Controls the Astrocyte Immunoregulatory Phenotype

Abstract

Astrocytes are the most abundant glial cells of the central nervous system and have recently been recognized as crucial in the regulation of brain immunity. In most neuropathological conditions, astrocytes are prone to a radical phenotypical change called reactivity, which plays a key role in astrocyte contribution to neuroinflammation. However, how astrocytes regulate brain immunity in healthy conditions is an understudied question. One of the astroglial molecule involved in these regulations might be Connexin 43 (Cx43), a gap junction protein highly enriched in astrocyte perivascular endfeet-terminated processes forming the glia limitans. Indeed, Cx43 deletion in astrocytes (Cx43KO) promotes a continuous immune recruitment and an autoimmune response against an astrocyte protein, without inducing any brain lesion. To investigate the molecular basis of this unique immune response, we characterized the polysomal transcriptome of hippocampal astrocytes deleted for Cx43. Our results demonstrate that, in the absence of Cx43, astrocytes adopt an atypical reactive status with no change in most canonical astrogliosis markers, but with an upregulation of molecules promoting immune recruitment, complement activation as well as anti-inflammatory processes. Intriguingly, while several of these upregulated transcriptional events suggested an activation of the γ-interferon pathway, no increase in this cytokine or activation of related signaling pathways were found in Cx43KO. Finally, deletion of astroglial Cx43 was associated with the upregulation of several angiogenic factors, consistent with an increase in microvascular density in Cx43KO brains. Collectively, these results strongly suggest that Cx43 controls immunoregulatory and angiogenic properties of astrocytes.

Astrocyte and Oligodendrocyte Cross-Talk in the Central Nervous System

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Melanoma‐derived extracellular vesicles instigate proinflammatory signaling in the metastatic microenvironment

“…Activated astrocytes mediate neuroinflammation and recruitment of immune cells to brain after tissue damage and in autoimmunity . Moreover, proinflammatory activation of astrocytes was demonstrated in brain tumors and metastases .…”

“…Activated astrocytes mediate neuroinflammation and recruitment of immune cells to brain after tissue damage and in autoimmunity. 32,33 Moreover, proinflammatory activation of astrocytes was demonstrated in brain tumors and metastases. 18,34 We therefore asked whether activation of proinflammatory signaling in astrocytes by melanoma-derived EVs will affect their capacity to facilitate immune cell recruitment.…”

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“…Of interest, one molecule highly concentrated in astrocytic end-feet is the gap junction protein, connexin 43 (Cx43) (158). Cx43 may have roles in the non-cell autonomous pathogenesis of sALS, implicating toxic mitochondria transferring from astrocytes to motor neurons at the BSCB (159, 160), as detailed below.…”