Escherichia Coli K1-colibactin meningitis induces microglial NLRP3/IL-18 exacerbating H3K4me3-synucleinopathy in human inflammatory gut-brain axis

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: March 6, 2025

Escherichia coli K1 (E. K1) meningitis early occurs in the gastrointestinal and causes severe damage to central nervous system, including lifelong neurological complications survivors. However, cellular mechanism by which E. may cause neuropathies is not well understood due lack of relevant human multi-organ models for studying multifaceted systemic inflammation across gut-brain axis. Here, we reconstruct a multicellular model axis identify neuropathogenic driven K1-colibactin meningitis. We observed that K1-genotoxic colibactin induced intestinal peripheral interleukin 6, causing blood-brain barrier injury endothelial via p38/p65 pathways. Serpin-E1 from damaged cerebral endothelia induces reactive astrocytes release IFN-γ, reduces microglial phagocytosis exacerbates detrimental neuroinflammation NLRP3/IL-18 Microglial IL-18 elevates neuronal oxidative stress worsens DNA double-strand breaks K1-infected neurons, leading H3K4 trimethylation phosphorylation alpha-synuclein. Our findings suggest therapeutic strategies post-bacterial treatment potentially prevent initiation synucleinopathy.

Language: Английский

sAstrocytic NLRP3 cKO mitigates depression-like behaviors induced by mild TBI in mice.

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: 205, P. 106785 - 106785

Published: Jan. 9, 2025

Reports indicate that depression is a common mental health issue following traumatic brain injury (TBI). Our prior research suggests Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-related neuroinflammation, modulated by glial cells such as astrocytes, likely to play crucial role in the progression of anxiety and cognitive dysfunction. However, there limited understanding potential astrocytic NLRP3 treating under mild TBI condition. This study aimed determine whether knockout (KO) could mitigate depressive-like behaviors explore variations between genders post-mild TBI. Mild was induced mice using Feeney's weight-drop method. Behavioral assessments included neurological severity scores (NSS), social interaction test (SI), tail suspension (TST), forced swimming (FST). Pathological changes were evaluated through immunofluorescence local field (LFP) recordings at various time points post-injury. findings indicated astrocyte-specific KO decreased cleaved caspase-1 colocalized with pathogenic astrocytes increased Postsynaptic density 95 (PSD95) intensity, significantly alleviated TBI-induced depression-like behaviors. It also led upregulation protective apoptosis-associated factors, including caspase-3 Additionally, deletion resulting improved θ γ power θ-γ phase coupling (SI). Notably, conditions, exhibited greater neuroprotective effects female compared males. Astrocyte demonstrated mechanism subjected TBI, possibly attributed inhibition pyroptosis signaling pathway astrocytes.

Language: Английский

STING Facilitates Vascular Calcification via p‐STAT1/NLRP3 Signal

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(7)

Published: April 7, 2025

ABSTRACT Vascular calcification is an independent predictor of cardiovascular mortality in patients with chronic kidney disease (CKD), yet no approved treatment exists. The cGAS‐STING signaling participates various diseases. Notably, DNA damage, important regulator vascular calcification, activates the signaling. However, it remains poorly understood whether STING regulates under CKD conditions. In current study, we showed that expression was elevated during calcification. knockdown or pharmacological inhibition decreased calcium deposits smooth muscle cells and human arterial rings, while its activation exacerbated Furthermore, knockout mice exhibited reduced aortic RNA sequencing analysis suggested STAT1 pathway may mediate STING‐induced phosphorylated (p‐STAT1) levels, p‐STAT1 mitigated VSMCs tissues. Additionally, downregulated NLRP3 expression, inhibiting further attenuated VSMC indicating accelerates via activation. Altogether, our study highlights STING/p‐STAT1/NLRP3 axis as a key mediator suggesting targeting represent promising therapeutic approach for patients.

Language: Английский