The inflammasome pathway is amplified and perpetuated in an autocrine manner through connexin43 hemichannel mediated ATP release

Mugisho, Odunayo O.; Green, Colin; Kho, Dan T; Zhang, Jie; Graham, Euan; Acosta, Mónica L.; Rupenthal, Ilva D.

doi:10.1016/j.bbagen.2017.11.015

Cited by 90 publications

(107 citation statements)

References 71 publications

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“…Astrocytes stimulated with gp120 for 24 h displayed a 4.5-fold and 6-fold rise in the secretion of IL-1β and TNF-α compared to untreated conditions, respectively ( Figure 5A,B). Contrary to prior evidence indicating that the activation of hemichannels and pannexons contributes to the production of cytokines [39,[52][53][54], we observed that Tat-L2, gap19 or 10 panx1 did not reduce the gp120-induced release of IL-1β and TNF-α. Increased iNOS activation and subsequent production of NO are downstream processes of IL-1β/TNF-α signaling and participate in reactive astrogliosis [55].…”

Section: The Gp120-induced Production Of No Is Partially Mediated By contrasting

confidence: 99%

HIV gp120 Protein Increases the Function of Connexin 43 Hemichannels and Pannexin-1 Channels in Astrocytes: Repercussions on Astroglial Function

Gajardo-Gómez

Santibáñez

Labra

et al. 2020

IJMS

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At least half of human immunodeficiency virus (HIV)-infected individuals suffer from a wide range of cognitive, behavioral and motor deficits, collectively known as HIV-associated neurocognitive disorders (HAND). The molecular mechanisms that amplify damage within the brain of HIV-infected individuals are unknown. Recently, we described that HIV augments the opening of connexin-43 (Cx43) hemichannels in cultured human astrocytes, which result in the collapse of neuronal processes. Whether HIV soluble viral proteins such as gp120, can regulate hemichannel opening in astrocytes is still ignored. These channels communicate the cytosol with the extracellular space during pathological conditions. We found that gp120 enhances the function of both Cx43 hemichannels and pannexin-1 channels in mouse cortical astrocytes. These effects depended on the activation of IL-1β/TNF-α, p38 MAP kinase, iNOS, cytoplasmic Ca2+ and purinergic signaling. The gp120-induced channel opening resulted in alterations in Ca2+ dynamics, nitric oxide production and ATP release. Although the channel opening evoked by gp120 in astrocytes was reproduced in ex vivo brain preparations, these responses were heterogeneous depending on the CA1 region analyzed. We speculate that soluble gp120-induced activation of astroglial Cx43 hemichannels and pannexin-1 channels could be crucial for the pathogenesis of HAND.

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Section: The Gp120-induced Production Of No Is Partially Mediated By contrasting

confidence: 99%

HIV gp120 Protein Increases the Function of Connexin 43 Hemichannels and Pannexin-1 Channels in Astrocytes: Repercussions on Astroglial Function

Gajardo-Gómez

Santibáñez

Labra

et al. 2020

IJMS

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“…Of note, astrocytes treated for 24 with these concentrations of IL-1β (2 ng/mL) and TNF-α (1 ng/mL) exhibited values of Etd uptake indistinguishable from those triggered by α-synuclein ( Figure SS1). Previous studies have related the opening of hemichannels and pannexons with the production and release of cytokines in diverse cell types (Mugisho et al, 2018;Parzych et al, 2017;Pelegrin & Surprenant, 2006), including astrocytes (Wei et al, 2016). In contrast to this evidence, we found that Tat-L2, gap19 or 10 panx1 failed in to prevent the α-synuclein-induced release of IL-1β and TNF-α, suggesting that Cx43 hemichannels and Panx1 channels are not implicated in this response.…”

Section: The α-Synuclein-mediated Release Of Gliotransmitters Depencontrasting

confidence: 99%

Connexin 43 hemichannels and pannexin‐1 channels contribute to the α‐synuclein‐induced dysfunction and death of astrocytes

Díaz

Labra

Alvear

et al. 2019

Glia

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Diverse studies have suggested that cytoplasmic inclusions of misfolded α‐synuclein in neuronal and glial cells are main pathological features of different α‐synucleinopathies, including Parkinson's disease and dementia with Lewy bodies. Up to now, most studies have focused on the effects of α‐synuclein on neurons, whereas the possible alterations of astrocyte functions and neuron–glia crosstalk have received minor attention. Recent evidence indicates that cellular signaling mediated by hemichannels and pannexons is critical for astroglial function and dysfunction. These channels constitute a diffusional route of communication between the cytosol and the extracellular space and during pathological scenarios they may lead to homeostatic disturbances linked to the pathogenesis and progression of different diseases. Here, we found that α‐synuclein enhances the opening of connexin 43 (Cx43) hemichannels and pannexin‐1 (Panx1) channels in mouse cortical astrocytes. This response was linked to the activation of cytokines, the p38 MAP kinase, the inducible nitric oxide synthase, cyclooxygenase 2, intracellular free Ca2+ concentration ([Ca2+]i), and purinergic and glutamatergic signaling. Relevantly, the α‐synuclein‐induced opening of hemichannels and pannexons resulted in alterations in [Ca2+]i dynamics, nitric oxide (NO) production, gliotransmitter release, mitochondrial morphology, and astrocyte survival. We propose that α‐synuclein‐mediated opening of astroglial Cx43 hemichannels and Panx1 channels might constitute a novel mechanism involved in the pathogenesis and progression of α‐synucleinopathies.

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“…Importantly, it is thought that Cx43 hemichannel opening may continue and propagate the inflammatory scene (Retamal et al, 2007;Guo et al, 2016;Li et al, 2018;Saez et al, 2018). In addition, upregulated Cx43 expression often correlates with increased inflammatory responses, while reduced Cx43 expression inhibits inflammation (Mori et al, 2006;Retamal et al, 2007;Cronin et al, 2008;Danesh-Meyer et al, 2008;Tsuchida et al, 2013;Mugisho et al, 2018). TAT-Gap19 has been demonstrated to significantly decrease IL-1β and TNF-α in non-alcoholic fatty liver mouse model (Willebrords et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage

et al. 2020

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Background: Emerging evidence indicates an excess risk of late occurring cardiovascular diseases, especially atherosclerosis, after thoracic cancer radiotherapy. Ionizing radiation (IR) induces cellular effects which may induce endothelial cell dysfunction, an early marker for atherosclerosis. In addition, intercellular communication through channels composed of transmembrane connexin proteins (Cxs), i.e. Gap junctions (direct cell-cell coupling) and hemichannels (paracrine release/uptake pathway) can modulate radiation-induced responses and therefore the atherosclerotic process. However, the role of endothelial hemichannel in IR-induced atherosclerosis has never been described before. Materials and Methods: Telomerase-immortalized human Coronary Artery/ Microvascular Endothelial cells (TICAE/TIME) were exposed to X-rays (0.1 and 5 Gy). Production of reactive oxygen species (ROS), DNA damage, cell death, inflammatory responses, and senescence were assessed with or without applying a Cx43 hemichannel blocker (TAT-Gap19). Results: We report here that IR induces an increase in oxidative stress, cell death, inflammatory responses (IL-8, IL-1β, VCAM-1, MCP-1, and Endothelin-1) and premature cellular senescence in TICAE and TIME cells. These effects are significantly reduced in the presence of the Cx43 hemichannel-targeting peptide TAT-Gap19. Conclusion: Our findings suggest that endothelial Cx43 hemichannels contribute to various IR-induced processes, such as ROS, cell death, inflammation, and senescence, resulting in an increase in endothelial cell damage, which could be protected by blocking these hemichannels. Thus, targeting Cx43 hemichannels may potentially exert radioprotective effects.

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The inflammasome pathway is amplified and perpetuated in an autocrine manner through connexin43 hemichannel mediated ATP release

Cited by 90 publications

References 71 publications

HIV gp120 Protein Increases the Function of Connexin 43 Hemichannels and Pannexin-1 Channels in Astrocytes: Repercussions on Astroglial Function

HIV gp120 Protein Increases the Function of Connexin 43 Hemichannels and Pannexin-1 Channels in Astrocytes: Repercussions on Astroglial Function

Connexin 43 hemichannels and pannexin‐1 channels contribute to the α‐synuclein‐induced dysfunction and death of astrocytes

Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage

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