Maternal P2X7 receptor inhibition prevents autism-like phenotype in male mouse offspring through the NLRP3-IL-1β pathway.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition caused by interactions of environmental and genetic factors. Recently we showed that activation of the purinergic P2X7 receptors is necessary and sufficient to convert maternal immune activation (MIA) to ASD-like features in male offspring mice. Our aim was to further substantiate these findings and identify downstream signaling pathways coupled to P2X7 upon MIA. Maternal treatment with the NLRP3 antagonist MCC950 and a neutralising IL-1β antibody during pregnancy counteracted the development of autistic characteristics in offspring mice. We also explored time-dependent changes of a widespread cytokine and chemokine profile in maternal blood and fetal brain samples of poly(I:C)/saline-treated dams. MIA-induced increases in plasma IL-1β, RANTES, MCP-1, and fetal brain IL-1β, IL-2, IL-6, MCP-1 concentrations are regulated by the P2X7/NLRP3 pathway. Offspring treatment with the selective P2X7 receptor antagonist JNJ47965567 was effective in the prevention of autism-like behavior in mice using a repeated dosing protocol. Our results highlight that in addition to P2X7, NLRP3, as well as inflammatory cytokines, may also be potential biomarkers and therapeutic targets of social deficits and repetitive behaviors observed in autism spectrum disorder.

Szabó D ，Tod P ，Gölöncsér F ，Román V ，Lendvai B ，Otrokocsi L ，Sperlágh B ... -  《-》

P2X7 Receptors Drive Poly(I:C) Induced Autism-like Behavior in Mice.

Maternal immune activation (MIA) is a principal environmental risk factor contributing to autism spectrum disorder (ASD), which compromises fetal brain development at critical periods of pregnancy and might be causally linked to ASD symptoms. We report that endogenous activation of the purinergic ion channel P2X7 (P2rx7) is necessary and sufficient to transduce MIA to autistic phenotype in male offspring. MIA induced by poly(I:C) injections to P2rx7 WT mouse dams elicited an autism-like phenotype in their offspring, and these alterations were not observed in P2rx7-deficient mice, or following maternal treatment with a specific P2rx7 antagonist, JNJ47965567. Genetic deletion and pharmacological inhibition of maternal P2rx7s also counteracted the induction of IL-6 in the maternal plasma and fetal brain, and disrupted brain development, whereas postnatal P2rx7 inhibition alleviated behavioral and morphological alterations in the offspring. Administration of ATP to P2rx7 WT dams also evoked autistic phenotype, but not in KO dams, implying that P2rx7 activation by ATP is sufficient to induce autism-like features in offspring. Our results point to maternal and offspring P2rx7s as potential therapeutic targets for the early prevention and treatment of ASD.SIGNIFICANCE STATEMENT Autism spectrum disorder (ASD) is a neurodevelopmental psychiatric disorder caused by genetic and environmental factors. Recent studies highlighted the importance of perinatal risks, in particular, maternal immune activation (MIA), showing strong association with the later emergence of ASD in the affected children. MIA could be mimicked in animal models via injection of a nonpathogenic agent poly(I:C) during pregnancy. This is the first report showing the key role of a ligand gated ion channel, the purinergic P2X7 receptor in MIA-induced autism-like behavioral and biochemical features. We show that genetic or pharmacological inhibition of both maternal and offspring P2X7 receptors could reverse the compromised brain development and autistic phenotype pointing to new possibilities for prevention and treatment of ASD.

Horváth G ，Otrokocsi L ，Beko K ，Baranyi M ，Kittel Á ，Fritz-Ruenes PA ，Sperlágh B ... -  《-》

Exogenous PD-L1 binds to PD-1 to alleviate and prevent autism-like behaviors in maternal immune activation-induced male offspring mice.

Zeng X ，Fan L ，Qin Q ，Zheng D ，Wang H ，Li M ，Jiang Y ，Wang H ，Liu H ，Liang S ，Wu L ，Liang S ... -  《-》

Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation.

Vuillermot S ，Luan W ，Meyer U ，Eyles D ... -  《Molecular Autism》

P2X(7) receptor inhibition attenuated sympathetic nerve sprouting after myocardial infarction via the NLRP3/IL-1β pathway.

Mounting evidence supports the hypothesis that inflammation modulates sympathetic sprouting after myocardial infarction (MI). The myeloid P2X7 signal has been shown to activate the nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a master regulator of inflammation. We investigated whether P2X7 signal participated in the pathogenesis of sympathetic reinnervation after MI, and whether NLRP3/interleukin-1β (IL-1β) axis is involved in the process. We explored the relationship between P2X7 receptor (P2X7 R) and IL-1β in the heart tissue of lipopolysaccharide (LPS)-primed naive rats. 3'-O-(4-benzoyl) benzoyl adenosine 5'-triphosphate (BzATP), a P2X7 R agonist, induced caspase-1 activation and mature IL-1β release, which was further neutralized by a NLRP3 inhibitor (16673-34-0). MI was induced by coronary artery ligation. Following infarction, a marked increase in P2X7 R was localized within infiltrated macrophages and observed in parallel with an up-regulation of NLRP3 inflammasome levels and the release of IL-1β in the left ventricle. The administration of A-740003 (a P2X7 R antagonist) significantly prevented the NLRP3/IL-1β increase. A-740003 and/or Anakinra (an IL-1 receptor antagonist) significantly reduced macrophage infiltration as well as macrophage-based IL-1β and NGF (nerve growth factor) production and eventually blunted sympathetic hyperinnervation, as assessed by the immunofluorescence of tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP 43). Moreover, the use of Anakinra partly attenuated sympathetic sprouting. This indicated that the effect of P2X7 on neural remodelling was mediated at least partially by IL-1β. The arrhythmia score of programmed electric stimulation was in accordance with the degree of sympathetic hyperinnervation. In vitro studies showed that BzATP up-regulated secretion of nerve growth factor (NGF) in M1 macrophages via IL-1β. Together, these data indicate that P2X7 R contributes to neural and cardiac remodelling, at least partly mediated by NLRP3/IL-1β axis. Therapeutic interventions targeting P2X7 signal may be a novel approach to ameliorate arrhythmia following MI.

Yin J ，Wang Y ，Hu H ，Li X ，Xue M ，Cheng W ，Wang Y ，Li X ，Yang N ，Shi Y ，Yan S ... -  《-》