Elane mediates neutrophil infiltration into the brain and neuroinflammation
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PROVIDER: PRJNA1132996 | ENA |
REPOSITORIES: ENA
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Project description:In CUMS mice, neutrophils can infiltrate brain parenchyma and induce neuroinflammatory responses. To identify potential mediators, we analyzed the gene expression profiles of bone marrow neutrophils from mice subjected to CUMS and compared them with those of control mice. Interestingly, among the genes notably associated with neutrophil functions were Elane and Mpo, the crucial granule proteins of neutrophils that mediate chronic inflammation. Our study demonstrated that neutrophil-specific Elane knockout reduced neutrophil infiltration into the brain parenchyma and alleviated neuroinflammation. Elane plays a critical role in modulating the influence of peripheral neutrophils on brain.
2024-12-17 | GSE271724 | GEO
Project description:Group 2 innate lymphoid cells (ILC2s) play a crucial role in allergic diseases by coordinating a complex network of various effector cell lineages involved in type 2 inflammation. However, their function in regulating airway neutrophil infiltration, a deleterious symptom of severe asthma, remains unknown. Here, we observed ILC2-dependent neutrophil accumulation in the bronchoalveolar lavage fluid (BALF) of allergic mice models. Chromatography followed by proteomics analysis identified the alarmin high mobility group box-1 (HMGB1) in the supernatant of lung ILC2s initiated neutrophil chemotaxis. Genetic perturbation of Hmgb1 in ILC2s reduced BALF neutrophil numbers and alleviated airway inflammation. HMGB1 was loaded onto the membrane of lipid droplets (LDs) released from activated lung ILC2s. Genetic inhibition of LD accumulation in ILC2s significantly decreased extracellular HMGB1 abundance and BALF neutrophil infiltration. These findings unveil a previously uncharacterized extracellular LD-mediated immune signaling delivery pathway by which ILC2s regulate airway neutrophil infiltration during allergic inflammation.
2024-09-21 | GSE245964 | GEO
Project description:Acute STING signaling from microglia and peripheral white blood cells drive neutrophil infiltration influencing brain injury
| PRJNA928375 | ENA
Project description:Introduction: The acute phase protein pentraxin 3 (PTX3) is known for its anti-inflammatory effects through downregulating neutrophil transmigration during peripheral inflammation. Furthermore, we have previously demonstrated a neuroprotective and neuroreparative effect of PTX3 after cerebral ischaemia. Here we investigated, to our knowledge for the first time, the role of PTX3 in neutrophil transmigration and neurotoxicity following lipopolysaccharide (LPS)-induced cerebral inflammation and cerebral ischaemia. Methods: Neutrophil transmigration through interleukin-1? (IL-1?) activated brain endothelium and neurotoxicity of neutrophils isolated from wild-type (WT) or PTX3 knock-out (KO) mice was assessed in vitro. Primary cortical neuronal death after treatment with transmigrated neutrophils was quantified by lactate dehydrogenase (LDH) assay. Cerebral inflammation or ischemia was induced in WT and PTX3 KO mice via intrastriatal LPS injection or by transient middle cerebral artery occlusion (MCAo) respectively. Subsequent neutrophil infiltration in the brain was assessed by immunohistochemistry and the expression of pro-inflammatory cytokines interleukin-6 (IL-6) and IL-1? by enzyme-linked immunosorbent assay (ELISA). Results: Neutrophils isolated from WT mice after intrastriatal LPS injection transmigrated significantly more through IL-1? activated brain endothelium compared to neutrophils from PTX3 KO mice. Transmigrated WT and PTX3 KO neutrophils were significantly more neurotoxic than corresponding non-transmigrated neutrophils; however, no significant differences in neurotoxicity between genotypes were observed. PTX3 reduced the number of transmigrated neutrophils to the brain after intrastriatal LPS injection. Furthermore, PTX3 KO mice showed significantly increased levels of neutrophils in the brain after LPS administration or in the ischaemic hemisphere after MCAo, compared to WT mice. Conclusion: Our study shows that PTX3 regulates neutrophil transmigration in the CNS during neuroinflammation, demonstrating the potential of PTX3 as an effective therapeutic target in neuroinflammatory conditions.
| S-EPMC6786895 | biostudies-literature
Project description:Excessive and unresolved neuroinflammation is part of the pathological cascade in brain injuries such as acute ischemia, as well as neurodegenerative diseases, including multiple sclerosis and Alzheimer’s disease. Particularly, timely resolution of inflammation is critical for the recovery and repair after brain injury. The nuclear factor-κB (NF-κB) signaling plays a central role in neuroinflammation through transcriptional induction of proinflammatory genes. Here, we report that TRIM9, a brain-specific member of the TRIpartite motif (TRIM) family with ubiquitin E3 ligase activity, is upregulated in the peri-infarct cortical areas of mouse brain upon ischemic stroke, and governs the resolution of NF-κB-mediated neuroinflammation. Mechanistically, neuronal TRIM9 sequestered β-TrCP, a component of the Skp-Cullin-F-box (SCF) E3 ligase complex, from ubiquitinating IκBα, thereby mitigating NF-κB-dependent inflammatory responses including production of proinflammatory mediators and infiltration of immune cells. Consequently, Trim9 deficient mice were highly vulnerable to ischemia, manifesting uncontrolled neuroinflammation and exacerbated neuropathological and neurological outcomes. Systemic administration of recombinant adeno-associated virus (AAV)-PHP.B, allowing brain-wide enriched TRIM9 expression, effectively resolved neuroinflammation and alleviated neuronal death in aging mice. This reveals that TRIM9 is essential for fine tuning of NF-κB-dependent neuroinflammation, and TRIM9-potentiation based therapy may offer a new approach for the treatment of stroke and inflammation-related neurological disorders.
2018-12-31 | GSE114652 | GEO
Project description:Endogenous retroviruses (ERVs) make up a large fraction of mammalian genome and are thought to contribute to human disease, including brain disorders. Aberrant activation of ERVs constitute a potential trigger for neuroinflammation, but mechanistic insight into this phenomenon remains unclear. Using CRISPR/Cas9-based gene disruption of the epigenetic co-repressor protein Trim28, we found a dynamic H3K9me3-dependent regulation of ERVs in proliferating neural progenitor cells (NPCs), but not in adult neurons. In vivo disruption of Trim28 in cortical NPCs during brain development resulted in viable offspring expressing high levels of ERVs in excitatory neurons in the adult brain of mice. Neuronal ERV expression was linked to inflammation, including activated microglia, and aggregates of ERV-derived proteins. This study demonstrates that brain development is a critical period for the silencing of ERVs and provides causal in vivo evidence demonstrating that transcriptional activation of ERV in neurons results in neuroinflammation.
2021-02-24 | GSE154196 | GEO
Project description:Hyperglycemia has been shown to modulate the immune response of peripheral immune cells and organs, but the impact of hyperglycemia on neuroinflammation within the brain remains elusive. In the present study, we provide evidences that streptozotocin (STZ)-induced hyperglycemic condition in mice drives a phenotypic switch of brain astrocytes to a proinflammatory and neurotoxic state, and increases brain vulnerability to mild peripheral inflammation. In particular, we found that hyperglycemia led to a significant increase in the astrocyte proliferation as determined by flow cytometric and immunohistochemical analyses of mouse brain. Transcriptomic analysis of isolated astrocytes from Aldh1l1CreER;tdTomato mice revealed that peripheral STZ injection induced astrocyte reprogramming into proliferative, proinflammatory and neurotoxic phenotype. Additionally, STZ-induced hyperglycemic condition significantly enhanced the infiltration of circulating myeloid cells into the brain and the disruption of blood-brain barrier in response to mild lipopolysaccharide (LPS) administration. Systemic hyperglycemia did not alter the intensity and sensitivity of peripheral inflammation in mice to LPS challenge, but increased the inflammatory potential of brain microglia. Furthermore, hyperglycemic mice exhibited a significant impairment in cognitive function after mild LPS administration compared to normoglycemic mice as determined by novel object recognition and Y-maze tasks. Taken together, these results demonstrate that hyperglycemia directly induces astrocyte reprogramming towards a proliferative and proinflammatory phenotype, which potentiates mild LPS-triggered inflammation within brain parenchymal regions.
2024-06-05 | GSE247033 | GEO
Project description:Neutrophil recruitment is pivotal to host defense against microbial infection, but also contributes to the immunopathology of disease. We investigated the mechanism of neutrophil recruitment in human infectious disease by bioinformatic pathways analysis of the gene expression profiles in the skin lesions of leprosy. In erythema nodosum leprosum (ENL), which occurs in patients with lepromatous leprosy (L-lep), and is characterized by neutrophil infiltration in lesions, the most overrepresented biologic functional group was “cell movement” including E-selectin, which was coordinately regulated with IL-1. In vitro activation of TLR2, upregulated in ENL lesions, triggered induction of IL-1, which together with IFN-, induced E-selectin expression on, and neutrophil adhesion to endothelial cells. Thalidomide, an effective treatment for ENL, inhibited this neutrophil recruitment pathway. The gene expression profile of ENL lesions comprised an integrated pathway of TLR2/FcR activation, neutrophil migration and inflammation, providing insight into mechanisms of neutrophil recruitment in human infectious disease. 6 ENL skin lesions and 7 Lepromatous leprosy skin lesions
2009-06-30 | E-GEOD-16844 | biostudies-arrayexpress
Project description:BackgroundThe secondary injury caused by traumatic brain injury (TBI), especially white matter injury (WMI), is highly sensitive to neuroinflammation, which further leads to unfavored long-term outcomes. Although the cross-talk between the three active events, immune cell infiltration, BBB breakdown, and proinflammatory microglial/macrophage polarization, plays a role in the vicious cycle, its mechanisms are not fully understood. It has been reported that cordycepin, an extract from Cordyceps militaris, can inhibit TBI-induced neuroinflammation although the long-term effects of cordycepin remain unknown. Here, we report our investigation of cordycepin's long-term neuroprotective function and its underlying immunological mechanism.MethodsTBI mice model was established with a controlled cortical impact (CCI) method. Cordycepin was intraperitoneally administered twice daily for a week. Neurological outcomes were assessed by behavioral tests, including grid walking test, cylinder test, wire hang test, and rotarod test. Immunofluorescence staining, transmission electron microscopy, and electrophysiology recording were employed to assess histological and functional lesions. Quantitative-PCR and flow cytometry were used to detect neuroinflammation. The tracers of Sulfo-NHS-biotin and Evans blue were assessed for the blood-brain barrier (BBB) leakage. Western blot and gelatin zymography were used to analyze protein activity or expression. Neutrophil depletion in vivo was performed via using Ly6G antibody intraperitoneal injection.ResultsCordycepin administration ameliorated long-term neurological deficits and reduced neuronal tissue loss in TBI mice. Meanwhile, the long-term integrity of white matter was also preserved, which was revealed in multiple dimensions, such as morphology, histology, ultrastructure, and electrical conductivity. Cordycepin administration inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization after TBI. BBB breach was attenuated by cordycepin administration at 3 days after TBI. Cordycepin suppressed the activities of MMP-2 and MMP-9 and the neutrophil infiltration at 3 days after TBI. Moreover, neutrophil depletion provided a cordycepin-like effect, and cordycepin administration united with neutrophil depletion did not show a benefit of superposition.ConclusionsThe long-term neuroprotective function of cordycepin via suppressing neutrophil infiltration after TBI, thereby preserving BBB integrity and changing microglia/macrophage polarization. These findings provide significant clinical potentials to improve the quality of life for TBI patients.
| S-EPMC8207641 | biostudies-literature
Project description:Activation of endogenous retroviruses during brain development causes neuroinflammation
| PRJNA645401 | ENA