Activation of inflammasomes, such as Nlrp3 and AIM2, can exacerbate atherosclerosis in mice and humans. Gasdermin D (GsdmD) serves as a final executor of inflammasome activity, by generating membrane pores for the release of mature Interleukin-1beta (IL-1β). Inflammation dampens reverse cholesterol transport (RCT) and promotes atherogenesis, while anti-IL-1β antibodies were shown to reduce cardiovascular disease in humans. Though Nlrp3/AIM2 and IL-1β nexus is an emerging atherogenic pathway, the direct role of GsdmD in atherosclerosis is not yet fully clear. Here, we used in vivo Nlrp3 inflammasome activation to show that the GsdmD–/– mice release ∼80% less IL-1β vs. Wild type (WT) mice. The GsdmD–/– macrophages were more resistant to Nlrp3 inflammasome mediated reduction in cholesterol efflux, showing ∼26% decrease vs. ∼60% reduction in WT macrophages. GsdmD expression in macrophages exacerbated foam cell formation in an IL-1β dependent fashion. The GsdmD–/– mice were resistant to Nlrp3 inflammasome mediated defect in RCT, with ∼32% reduction in plasma RCT vs. ∼57% reduction in WT mice, ∼17% reduction in RCT to liver vs. 42% in WT mice, and ∼37% decrease in RCT to feces vs. ∼61% in WT mice. The LDLr antisense oligonucleotides (ASO) induced hyperlipidemic mouse model showed the role of GsdmD in promoting atherosclerosis. The GsdmD–/– mice exhibit ∼42% decreased atherosclerotic lesion area in females and ∼33% decreased lesion area in males vs. WT mice. The atherosclerotic plaque-bearing sections stained positive for the cleaved N-terminal fragment of GsdmD, indicating cleavage of GsdmD in atherosclerotic plaques. Our data show that GsdmD mediates inflammation-induced defects in RCT and promotes atherosclerosis.

The mammalian brain constantly adapts to new experiences of the environment, and inhibitory circuits play a crucial role in this experience-dependent plasticity. A characteristic feature of inhibitory neurons is the establishment of electrical synapses, but the function of electrical coupling in plasticity is unclear. Here we show that elimination of electrical synapses formed by connexin36 altered inhibitory efficacy and caused frequency facilitation of inhibition consistent with a decreased GABA release in the inhibitory network. The altered inhibitory efficacy was paralleled by a failure of theta-burst long-term potentiation induction and by impaired ocular dominance plasticity in the visual cortex. Together, these data suggest a unique mechanism for regulating plasticity in the visual cortex involving synchronization of inhibitory networks via electrical synapses.gap junctions | development | cannabinoid receptor 1 | synchrony S ynaptic interactions in the mammalian brain are sculpted by experience, particularly during "critical periods" in development. Accumulating evidence suggests that inhibitory neurons play a crucial role in reshaping neural networks in response to sensory perturbations (1). Inhibitory neurons in many areas of the brain, including the cerebral cortex, are coupled via gap junctions containing connexin36 (Cx36), which allow subthreshold fluctuations in membrane potential to spread between cells and promote synchrony of firing (2-5). Cx36-null mice (Cx36KO) display decreased coherence of rhythmic activity in populations of cortical interneurons in brain slices and decreased strength of evoked cortical inhibition in vivo (6-8). Similar effects of Cx36 signaling might underlie the behavioral deficits in cerebellar learning tasks in Cx36KO (7). However, the possible functions of Cx36 in sensory cortical development and plasticity are unknown.A common model for experience-dependent synaptic modification is ocular dominance (OD) plasticity of visual cortex. In the visual cortex, decreasing neural activity in one eye (monocular deprivation; MD) leads to weakening and removal of connections representing the deprived eye (DE) and strengthening and expansion of connections representing the nondeprived eye (NDE; refs. 9-13). These manipulations are particularly effective during the critical period, which extends from postnatal day (P) 19 to ∼P55 and peaks at ∼P25-28 in mice (11,14,15). Both inhibition and synaptic plasticity mechanisms, such as long-term potentiation (LTP) and long-term depression (LTD), play a key role in OD plasticity, and inhibition can alter synaptic plasticity (1,16,17). Cx36 is present in most cortical layers during the critical period for OD plasticity (6). We therefore investigated to what degree Cx36 controls inhibitory function and, consequently, synaptic and OD plasticity.Here we report altered dynamics of the evoked inhibitory synaptic currents in mice lacking Cx36, such that there is a reduction when probed at low-frequency stimulation but a facilitation at higher frequ...

Nlrp3 inflammasome is activated in advanced human atherosclerotic plaques. Gasdermin D (GsdmD) serves as a final executor of Nlrp3 inflammasome activity, by generating membrane pores for the release of mature Interleukin-1beta (IL-b). Inflammation dampens reverse cholesterol transport (RCT) and promotes atherogenesis, while anti-IL-1b; antibodies were shown to reduce cardiovascular disease in humans. Though Nlrp3/IL-1b; nexus is an emerging atherogenic pathway, the direct role of GsdmD in atherosclerosis is not yet clear. Here, we used in-vivo Nlrp3 inflammasome activation to show that the GsdmD-/- mice release ~80% less IL-1b; vs WT mice. The GsdmD-/- macrophages were more resistant to Nlrp3 inflammasome mediated reduction in cholesterol efflux, showing ~26% decrease vs. ~60% reduction in WT macrophages. GsdmD expression in macrophages exacerbated foam cell formation in an IL-1b; dependent fashion. The GsdmD-/- mice were resistance to Nlrp3 inflammasome mediated defect in RCT, with ~32% reduction in plasma RCT vs. ~ 57% reduction in WT mice, ~ 17% reduction in RCT to liver vs. 42% in WT mice, and ~ 37% decrease in RCT to feces vs. ~ 61% in WT mice. The LDLr anti-sense oligonucleotides (ASO) induced hyperlipidemic mouse model showed role of GsdmD in promoting atherosclerosis. The GsdmD-/- mice exhibit ~42% decreased atherosclerotic lesion area in females and ~33% decreased lesion area in males vs. WT mice. The atherosclerotic plaque-bearing WT mice showed the presence of cleaved N-terminal fragment of GsdmD, indicating cleavage of GsdmD during atherosclerosis. Our data show that GsdmD mediates inflammation-induced defect in RCT and promotes atherosclerosis.

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