Increased expression of the ATP‐gated P2X7 receptor reduces responsiveness to anti‐convulsants during status epilepticus in mice

Shi

Clinical & Translational Med

et al. 2022

Sepsis remains the most lethal infectious disease and substantially impairs patient prognosis after liver transplantation (LT). Our previous study reported a role of the pannexin 1 (PANX1)–interleukin‐33 (IL‐33) axis in activating innate immunity to protect against methicillin‐resistant Staphylococcus aureus infection; however, the role of PANX1 in regulating adaptive immunity in sepsis and the underlying mechanism are unclear. In this study, we examined the role of the PANX1–IL‐33 axis in protecting against sepsis caused by a gram‐negative bacterial infection in an independent LT cohort. Next, in animal studies, we assessed the immunological state of Panx1−/‐ mice with lipopolysaccharide (LPS)‐induced endotoxemia and then focused on the cytokine storm and regulatory T cells (Tregs), which are crucial for the resolution of inflammation. To generate liver‐specific Panx1‐deficient mice and mimic clinical LT procedures, a mouse LT model was established. We demonstrated that hepatic PANX1 deficiency exacerbated LPS‐induced endotoxemia and dysregulated the immune response in the mouse LT model. In hepatocytes, we confirmed that PANX1 positively regulated IL‐33 synthesis after LPS administration. We showed that the adenosine triphosphate‐P2X7 pathway regulated the hepatic PANX1–IL‐33 axis during endotoxemia in vitro and in vivo. Recombinant IL‐33 treatment rescued LPS‐induced endotoxemia by increasing the numbers of liver‐infiltrating ST2+ Tregs and attenuating the cytokine storm in hepatic PANX1‐deficient mice. In conclusion, our findings revealed that the hepatic PANX1–IL‐33 axis protects against endotoxemia and liver injury by targeting ST2+ Tregs and promoting the early resolution of hyperinflammation.

Section: Discussionsupporting

confidence: 93%

Hepatic pannexin‐1 mediates ST2⁺ regulatory T cells promoting resolution of inflammation in lipopolysaccharide‐induced endotoxemia

Shi

Clinical & Translational Med

et al. 2022

“…The presence of P2X7R in nerve terminals is controversial probably reflecting region-specific or pathologyassociated neuronal expression. Upregulation of the P2X7R expression has also been verified in the hippocampus and cortex of animal models (Engel et al, 2012a;Jimenez-Pacheco et al, 2013Barros-Barbosa et al, 2015Morgan et al, 2020) contributing to resistance to pharmacotherapy during status epilepticus (Beamer et al, 2021). The neocortex of human patients with TLE also overexpress the P2X7R (Jimenez-Pacheco et al, 2013Barros-Barbosa et al, 2016), but there is a gap in our knowledge concerning the location of this in the human hippocampus.…”

Section: Introductionmentioning

confidence: 99%

Mesial Temporal Lobe Epilepsy (MTLE) Drug-Refractoriness Is Associated With P2X7 Receptors Overexpression in the Human Hippocampus and Temporal Neocortex and May Be Predicted by Low Circulating Levels of miR-22

Leal

Barros‐Barbosa²,

Ferreirinha³

et al. 2022

Front. Cell. Neurosci.

Objective: ATP-gated ionotropic P2X7 receptors (P2X7R) actively participate in epilepsy and other neurological disorders. Neocortical nerve terminals of patients with Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (MTLE-HS) express higher P2X7R amounts. Overexpression of P2X7R bolsters ATP signals during seizures resulting in glial cell activation, cytokines production, and GABAergic rundown with unrestrained glutamatergic excitation. In a mouse model of status epilepticus, increased expression of P2X7R has been associated with the down-modulation of the non-coding micro RNA, miR-22. MiR levels are stable in biological fluids and normally reflect remote tissue production making them ideal disease biomarkers. Here, we compared P2X7R and miR-22 expression in epileptic brains and in the serum of patients with MTLE-HS, respectively.Methods: Quantitative RT-PCR was used to evaluate the expression of P2X7R in the hippocampus and anterior temporal lobe of 23 patients with MTLE-HS and 10 cadaveric controls. Confocal microscopy and Western blot analysis were performed to assess P2X7R protein amounts. MiR-22 expression was evaluated in cell-free sera of 40 MTLE-HS patients and 48 healthy controls.Results: Nerve terminals of the hippocampus and neocortical temporal lobe of MTLE-HS patients overexpress (p < 0.05) an 85 kDa P2X7R protein whereas the normally occurring 67 kDa receptor protein dominates in the brain of the cadaveric controls. Contrariwise, miR-22 serum levels are diminished (p < 0.001) in MTLE-HS patients compared to age-matched control blood donors, a situation that is more evident in patients requiring multiple (>3) anti-epileptic drug (AED) regimens.Conclusion: Data show that there is an inverse relationship between miR-22 serum levels and P2X7R expression in the hippocampus and neocortex of MTLE-HS patients, which implies that measuring serum miR-22 may be a clinical surrogate of P2X7R brain expression in the MTLE-HS. Moreover, the high area under the ROC curve (0.777; 95% CI 0.629–0.925; p = 0.001) suggests that low miR-22 serum levels may be a sensitive predictor of poor response to AEDs among MTLE-HS patients. Results also anticipate that targeting the miR-22/P2X7R axis may be a good strategy to develop newer AEDs.

“…P2X7R knockout or antagonism leads to lower levels of the proconvulsive cytokine IL-1β in the hippocampus following i.a. KA-induced status epilepticus [112,126] and reduces microgliosis and astrogliosis during epilepsy [122]. In line with the effects of P2X7R being mediated via its effects on microglia, we recently showed that P2X7R expression was increased in microglia during status epilepticus, at a time point when responses to anticonvulsants are reduced, and that P2X7R overexpression led to a pro-inflammatory phenotype in microglia during status epilepticus [112,126].…”

Section: Targeting Of the P2x7r And Seizure Controlmentioning

confidence: 64%

“…Further in line with a proconvulsant function of P2X7Rs, Beamer et al showed in a recent study that increased P2X7R expression leads to drug-refractoriness during i.a. KA-induced status epilepticus [126]. In other seizure models, including lithium-pilocarpine-induced status epilepticus, the maximal electroshock seizure threshold test and the PTZ seizure threshold test in mice failed, however, to replicate these anticonvulsant effects [118,127].…”

Section: Targeting Of the P2x7r And Seizure Controlmentioning

confidence: 98%

“…KA-induced status epilepticus [112,126] and reduces microgliosis and astrogliosis during epilepsy [122]. In line with the effects of P2X7R being mediated via its effects on microglia, we recently showed that P2X7R expression was increased in microglia during status epilepticus, at a time point when responses to anticonvulsants are reduced, and that P2X7R overexpression led to a pro-inflammatory phenotype in microglia during status epilepticus [112,126]. Moreover, the same study showed that pre-treatment of mice with Lipopolysaccharide increased P2X7R levels in the brain and reduced responsiveness to anticonvulsants during status epilepticus, which was overcome by either a genetic deletion of the P2X7R or the administration of P2X7R antagonists [126].…”

Section: Targeting Of the P2x7r And Seizure Controlmentioning

confidence: 99%

See 1 more Smart Citation

Beyond Seizure Control: Treating Comorbidities in Epilepsy via Targeting of the P2X7 Receptor

Gil

Smith

Tang

et al. 2022

IJMS

Self Cite

Epilepsy is one of the most common chronic diseases of the central nervous system (CNS). Treatment of epilepsy remains, however, a clinical challenge with over 30% of patients not responding to current pharmacological interventions. Complicating management of treatment, epilepsy comes with multiple comorbidities, thereby further reducing the quality of life of patients. Increasing evidence suggests purinergic signalling via extracellularly released ATP as shared pathological mechanisms across numerous brain diseases. Once released, ATP activates specific purinergic receptors, including the ionotropic P2X7 receptor (P2X7R). Among brain diseases, the P2X7R has attracted particular attention as a therapeutic target. The P2X7R is an important driver of inflammation, and its activation requires high levels of extracellular ATP to be reached under pathological conditions. Suggesting the therapeutic potential of drugs targeting the P2X7R for epilepsy, P2X7R expression increases following status epilepticus and during epilepsy, and P2X7R antagonism modulates seizure severity and epilepsy development. P2X7R antagonism has, however, also been shown to be effective in treating conditions most commonly associated with epilepsy such as psychiatric disorders and cognitive deficits, which suggests that P2X7R antagonisms may provide benefits beyond seizure control. This review summarizes the evidence suggesting drugs targeting the P2X7R as a novel treatment strategy for epilepsy with a particular focus of its potential impact on epilepsy-associated comorbidities.