Connexin-43 hemichannels orchestrate NOD-like receptor protein-3 (NLRP3) inflammasome activation and sterile inflammation in tubular injury

Alzheimer’s disease (AD) is the major cause of senile dementia without effective therapeutic strategies. The fundamental role of microglia in AD pathology, particularly in the early stages, is well acknowledged, although cell-specific therapeutic targets were not identified. Here we show that microglial connexin 43 (Cx43) hemichannels controls microglial reactivity in AD, thus being a promising therapeutic target. We discovered a marked increase in Cx43 protein in the periplaque microglia in the post-mortem tissue from AD patients. Subsequently, using the APPswe/PS1dE9mouse model of AD, we demonstrated that microglial Cx43 operating as hemichannels influences microglial function, which in turn affects β-amyloid pathology. Ablation of microglial Cx43 hemichannels by genetic knockout shifted microglia to neuroprotective phenotype, which promoted the microglia-plaque interaction while suppressing the neurotoxic microglial signature, thereby mitigating the progression of AD. Following this lead, we developed a novel formulation of a small molecule peptide, lipid nanoparticle-delivered molecule TAT-Cx43266-283(TAT-CX43@LNPs), which selectively blocks Cx43 hemichannels. Our preclinical trial demonstrated its efficacy in delaying and rescuing β-amyloid-related neuropathology and cognitive impairment in AD mice. This study provides strong evidence to progress our novel drug into clinical trials and translate it to disease-preventing (when administered in the early disease stages) and disease-modifying agents.

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Endothelial-specific deletion of connexin 43 improves renal function and structure after acute kidney injury

Genest,

Kinugasa,

Roger

et al. 2024

Mol Med

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Background We have previously reported that the gap junction protein connexin 43 (Cx43) was upregulated in chronic renal disease in humans and rodents and plays a crucial role in the progression of experimental nephropathy. In this study, we investigated its role after renal ischemia/reperfusion (rIR), which is a major mechanism of injury in acute renal injury (AKI) and renal transplant graft dysfunction. Methods Wild-type mice (WT) and mice in which Cx43 expression was genetically reduced by half (Cx43 ±) were unilaterally nephrectomized. The left renal artery was subsequently clamped, with reperfusion of varying duration. Mice with tubular- or endothelial-specific deletion of Cx43 were also used to assess the effect of this connexin in each cell type after rIR. Kidneys were assessed for histological evaluation, immunohistochemistry, and RT-PCR. Results Blood urea nitrogen and creatininemia were progressively elevated in WT mice and picked up 48 h after rIR. At the same time point, severe tubular necrosis and dilation occurred in the cortico-medullary junction of the injured kidneys with accompanying massive neutrophil infiltration. Interestingly, Cx43 expression was progressively increased within the tubulointerstitial compartment during kidney damage progression and was paralleled closely by that of markers of renal dysfunction. Cx43 ± mice showed fewer tubular lesions, less inflammation, and further improved renal function. Similar results were observed in mice where Cx43 was specifically deleted within the vascular endothelium. In contrast, Cx43 deletion in renal tubules did not significantly improve renal structure and function after rIR. Conclusion Our findings suggest that endothelial Cx43 plays a crucial role in AKI.

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Connexin-43 hemichannels orchestrate NOD-like receptor protein-3 (NLRP3) inflammasome activation and sterile inflammation in tubular injury

Cited by 8 publications

References 67 publications

Boswellic acid and apigenin alleviate methotrexate-provoked renal and hippocampal alterations in rats: Targeting autophagy, NOD-2/NF-κB/NLRP3, and connexin-43

Boswellic acid and apigenin alleviate methotrexate-provoked renal and hippocampal alterations in rats: Targeting autophagy, NOD-2/NF-κB/NLRP3, and connexin-43

Turning microglia neuroprotective: Towards connexin43-specific therapy of Alzheimer’s disease

Endothelial-specific deletion of connexin 43 improves renal function and structure after acute kidney injury

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