NLRP3 inflammasome regulates astrocyte transformation in brain injury induced by chronic intermittent hypoxia

Abstract

Background Obstructive sleep apnea (OSA) is mainly characterized by sleep fragmentation and chronic intermittent hypoxia (CIH), the latter one being associated with multiple organ injury. Recently, OSA-induced cognition dysfunction has received extensive attention from scholars. Astrocytes are essential in neurocognitive deficits via A1/A2 phenotypic changes. Nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome is considered the most important factor inducing and maintaining neuroinflammation. However, whether the NLRP3 regulates the A1/A2 transformation of astrocytes in CIH-related brain injury remains unclear. Methods We constructed an OSA-related CIH animal model and assessed the rats' learning ability in the Morris water maze; the histopathological assessment was performed by HE and Nissl staining. The expression of GFAP (astrocyte marker), C3d (A1-type astrocyte marker), and S100a10 (A2-type astrocyte marker) were detected by immunohistochemistry and immunofluorescence. Western blotting and RT-qPCR were used to evaluate the changes of A1/A2 astrocyte-related protein and NLRP3/Caspase-1/ASC/IL-1β. Results The learning ability of rats decreased under CIH. Further pathological examination revealed that the neurocyte in the hippocampus were damaged. The cell nuclei were fragmented and dissolved, and Nissl bodies were reduced. Immunohistochemistry showed that astrocytes were activated, and morphology and number of astrocytes changed. Immunofluorescence, Western blotting and RT-qPCR showed that the expression of C3d was increased while S100a10 was decreased. Also, the expression of the inflammasome (NLRP3/Caspase-1/ASC/IL-1β) was increased. After treatment of MCC950 (a small molecule inhibitor of NLRP3), the damage of nerve cells was alleviated, the Nissl bodies increased, the activation of astrocytes was reduced, and the expression of A2-type astrocytes was increased. In contrast, A1-type astrocytes decreased, and the expression of inflammasome NLRP3/Caspase-1/ASC/IL-1β pathway-related proteins decreased. Conclusion The NLRP3 inflammasome could regulate the A1/A2 transformation of astrocytes in brain injury induced by CIH

Obstructive Sleep Apnea-Associated Intermittent Hypoxia-Induced Immune Responses in Males, Pregnancies, and Offspring

“…OSA alters exosomal carriers in circulation, especially miRNAs, and promotes endothelial dysfunction [68]. Several in vivo studies have demonstrated the involvement of miRNAs and the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome in chronic IH-induced inflammation and tissue injury [36, [69][70][71][72][73][74][75]. During IH exposures, miRNAs such as miR-155 [69], miR-210 [70], and miR-144 [71] are upregulated in renal tissue, endothelium, and serum-derived extracellular vesicles, respectively; the silencing of these miRNAs ameliorate IH-induced inflammation, endothelial dysfunction, and tissue injury [69][70][71].…”

“…In animal models, chronic IH exposure increases NLRP3 inflammasome expression, and NLRP3 deficiency or inhibition protects against IH-induced inflammation, oxidative stress, and apoptosis in the brain, heart, and vasculature [36, [72][73][74][75]. Additionally, in vitro IH exposure fails to induce IL-1β overproduction in bone marrow-derived macrophages isolated from NLRP3 knockout male mice [87], reinforcing the involvement of NLRP3 in IH-induced inflammation.…”

Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease

“…Conversely, the "neuroprotective" phenotype of astrocytes promotes neuronal survival and homeostasis, as these astrocytes secrete neurotrophic factors and anti-inflammatory cytokines [184,187,188]. Currently, published studies suggest that NLRP3 inflammasome activation and subsequent secretion of IL-18 and IL-1β from microglia drives astrocytes into the neurotoxic reactive state, which induces upregulation of the secretion of the complement protein C3 and results in lower synapse numbers [180,[189][190][191]. However, these studies evaluated astrocyte state upon NLRP3 inflammasome activation based on the binary "A1/A2" astrocyte description, which does not fully capture the diversity of astrocyte states and phenotypes in different contexts [183].…”

Summary of drug therapy to treat cognitive impairment-induced obstructive sleep apnea

“…Then, it leads to the release of caspase-1 and IL-1β ( He et al, 2016 ). A recent study indicated that the NLRP3 inflammasome expression was increased in the brain tissue after IH treatment ( She et al, 2022 ). Meanwhile, NLRP3 deletion elicited neuroprotection against IH treatment eliminating damaged mitochondria and reducing oxidative stress levels ( Wu et al, 2021 ).…”