Acute Neuroinflammation Research Articles

Mapping acute neuroinflammation in vivo with diffusion-MRI in rats given a systemic lipopolysaccharide challenge

It is becoming increasingly apparent that neuroinflammation plays a critical role in an array of neurological and psychiatric disorders. Recent studies have demonstrated the potential of diffusion MRI (dMRI) to characterize changes in microglial density and morphology associated with neuroinflammation, but these were conducted mostly ex vivo and/or in extreme, non-physiological animal models. Here, we build upon these studies by investigating the utility of well-established dMRI methods to detect neuroinflammation in vivo in a more clinically relevant animal model of sickness behavior. We show that diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) indicate widespread increases in diffusivity in the brains of rats given a systemic lipopolysaccharide challenge (n = 20) vs. vehicle-treated controls (n = 12). These diffusivity changes correlated with histologically measured changes in microglial morphology, confirming the sensitivity of dMRI to neuroinflammatory processes. This study marks a further step towards establishing a noninvasive indicator of neuroinflammation, which would greatly facilitate early diagnosis and treatment monitoring in various neurological and psychiatric diseases.

Retinal microvascular abnormalities in major depression.

The aim of our study was to find a possible association between retinal microvascular abnormality and major depression in a non-geriatric population. The participants with major depression were hospitalised at the University Hospital in Hradec Kralove, Department of Psychiatry. Retinal images were obtained using a stationary Fundus camera FF450 by Zeiss and a hand-held camera by oDocs. Fifty patients (men n=18, women n=32) aged 16 to 55 (men's average age 33.7±9.9 years, women's average age 37.9±11.5 years) were compared with fifty mentally healthy subjects (men n=28, women n=22) aged 18 to 61 (men's average age 35.3±9.2 years, women's average age 36.6±10.6 years) in a cross-sectional design. The patients were diagnosed with a single depressive episode (n=26) or a recurrent depressive disorder (n=24) according to the ICD-10 classification. Our results confirmed significant microvascular changes in the retina in patients with depressive disorder in comparison to the control group of mentally healthy subjects, with significantly larger arteriolar (P<0.0001) as well as venular (P<0.001-0.0001) calibres in major depression. According to the literature, acute and chronic neuroinflammation is associated with changes in microvascular form and function. The endothelium becomes a major participant in the inflammatory response damaging the surrounding tissue and its function. Because the retina and brain tissue share a common embryonic origin, we suspect similar microvascular pathology in the retina and in the brain in major depression. Our results may contribute to a better understanding of depression etiopathogenesis and to its personalized treatment.

Microglia play an important role in PRV infection-induced immune responses of the central nervous system

Pseudorabies virus (PRV) can infect multiple hosts and lead to fatal encephalitis. There is a significant increase in the number of microglia in the brain of animals infected with PRV. However, whether and how microglia contribute to central nervous system damage in PRV infection remain unknown. In the present study, we elucidated that PRV infection can cause more severe inflammatory cell infiltration, thicker and more numerous vessel sleeve walls, and more severe inflammatory responses in the brains of natural hosts (pigs) than in those of nonnatural hosts (mice). In a mice infection model, activated microglia restricted viral replication in the early stage of infection. Acute neuroinflammation caused by microglia hyperactivation at late-stage of infection. Furthermore, in vitro experiments revealed that microglia restricted viral replication and decreased viral infectivity. This may be associated with the phagocytic ability of microglia because we observed a significant increase in the expression of the membrane receptor TREM2 in microglia, which is closely related to phagocytosis, we observed that depletion of microglia exacerbated neurological symptoms, blood–brain barrier breakdown, and peripheral lymphocyte infiltration. Taken together, we revealed the dual role of microglia in protecting the host and neurons from PRV infection.

Co-transplantation of autologous Treg cells in a cell therapy for Parkinson's disease.

The specific loss of midbrain dopamine neurons (mDANs) causes major motor dysfunction in Parkinson's disease, which makes cell replacement a promising therapeutic approach1-4. However, poor survival of grafted mDANs remains an obstacle to successful clinical outcomes5-8. Here we show that the surgical procedure itself (referred to here as 'needle trauma') triggers a profound host response that is characterized by acute neuroinflammation, robust infiltration of peripheral immune cells and brain cell death. When midbrain dopamine (mDA) cells derived from human induced pluripotent stem (iPS) cells were transplanted into the rodent striatum, less than 10% of implanted tyrosine hydroxylase (TH)+ mDANs survived at two weeks after transplantation. By contrast, TH- grafted cells mostly survived. Notably, transplantation of autologous regulatory T (Treg) cells greatly modified the response to needle trauma, suppressing acute neuroinflammation and immune cell infiltration. Furthermore, intra-striatal co-transplantation of Treg cells and human-iPS-cell-derived mDA cells significantly protected grafted mDANs from needle-trauma-associated death and improved therapeutic outcomes in rodent models of Parkinson's disease with 6-hydroxydopamine lesions. Co-transplantation with Treg cells also suppressed the undesirable proliferation of TH- grafted cells, resulting in more compact grafts with a higher proportion and higher absolute numbers of TH+ neurons. Together, these data emphasize the importance of the initial inflammatory response to surgical injury in the differential survival of cellular components of the graft, and suggest that co-transplanting autologous Treg cells effectively reduces the needle-trauma-induced death of mDANs, providing a potential strategy to achieve better clinical outcomes for cell therapy in Parkinson's disease.

Ambiguous Contribution of Glucocorticosteroids to Acute Neuroinflammation in the Hippocampus of Rat.

Effects of modulation of glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) on acute neuroinflammatory response were studied in the dorsal (DH) and ventral (VH) parts of the hippocampus of male Wistar rats. Local neuroinflammatory response was induced by administration of bacterial lipopolysaccharide (LPS) to the DH. The modulation of GR and MR was performed by dexamethasone (GR activation), mifepristone, and spironolactone (GR and MR inhibition, respectively). Experimental drugs were delivered to the dentate gyrus of the DH bilaterally by stereotaxic injections. Dexamethasone, mifepristone, and spironolactone were administered either alone (basal conditions) or in combination with LPS (neuroinflammatory conditions). Changes in expression levels of neuroinflammation-related genes and morphology of microglia 3 days after intrahippocampal administration of above substances were assessed. Dexamethasone alone induced a weak proinflammatory response in the hippocampal tissue, while neither mifepristone nor spironolactone showed significant effects. During LPS-induced neuroinflammation, GR activation suppressed expression of selected inflammatory genes, though it did not prevent appearance of activated forms of microglia. In contrast to GR activation, GR or MR inhibition had virtually no influence on LPS-induced inflammatory response. The results suggest glucocorticosteroids ambiguously modulate specific aspects of neuroinflammatory response in the hippocampus of rats at molecular and cellular levels.

Tamibarotene targets heparin-binding protein for attenuating lung injury in sepsis.

Excessively active pulmonary inflammation is a hallmark of sepsis-induced lung damage. A synthetic retinoid drug called tamibarotene reduces inflammation in a variety of conditions, including acute promyelocytic leukemia (APL), renal fibrosis, and neuroinflammation. Its effect on sepsis-related lung injury, however, has not been explained. The purpose of the study was to investigate how tamibarotene affected lung damage induced by cecal ligation and puncture (CLP) procedure. A CLP sepsis mouse model was developed, and tamibarotene was pretreated to determine whether it improved lung injury and survival. The degree of lung injury was evaluated using the Hematoxylin and eosin staining and lung injury score. In order to determine pulmonary vascular permeability, measurements were taken for total protein and cell content of bronchoalveolar lavage fluid (BALF), wet/dry ratio of the lung, and Evans blue stain. The BALF inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, and IL-17A were discovered by enzyme-linked immunosorbent serologic assay (ELISA). Then, the levels of heparin-binding protein (HBP), and phospho-nuclear factor kappa-B (p-NF-κB) P65, and NF-κB P65 were determined using ELISA and Western blot analysis, respectively. Tamibarotene considerably increases survival and lessens lung damage stimulated by sepsis. Specifically, tamibarotene significantly relieves pulmonary vascular permeability and inhibits inflammation response in sepsis. Moreover, we further confirmed that these ameliorating effects of tamibarotene on sepsis may be exerted by targeting HBP and regulating the activation of NF-κB signaling pathway. These findings demonstrated that tamibarotene lessens sepsis-induced lung injury, and the effect could be exerted by targeting HBP and thereby deregulating the NF-κB signaling pathway.

Understanding sedative effects within the context of acute neuroinflammation in the developing brain: Potential induction of delirium-like behaviors

Neurologic morbidity is highly prevalent in pediatric critical illness, and the use of benzodiazepines and/or opioids is a risk factor for delirium and post-discharge sequelae. However, little is known about how multidrug sedation with these medications interacts with inflammation in the developing brain, a frequent condition during childhood critical illness that has not been extensively studied. In weanling rats, mild-moderate inflammation was induced with lipopolysaccharide (LPS) on postnatal day (P)18 and combined with 3 days repeated opioid and benzodiazepine sedation using morphine and midazolam (MorMdz) between P19–21. Delirium-like behaviors including abnormal response to whisker stimulation, wet dog shakes, and delay in finding buried food were induced in male and female rat pups treated with LPS, MorMdz, or LPS/MorMdz (n ≥ 17/group) and were compared using a z-score composite. Composite behavior scores were significantly increased in LPS, MorMdz, and LPS/MorMdz groups compared to saline control (F3,78 = 38.1, p < 0.0001). Additionally, expression of glial-associated neuroinflammatory markers ionized calcium-binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) in western blots of P22 brain homogenate were significantly higher after LPS than after LPS/MorMdz (Iba1, p < 0.0001; GFAP, p < 0.001). Likewise, proinflammatory cytokines were increased in brains of LPS-treated pups versus Saline (p = 0.002), but not LPS/MorMdz-treated pups (p = 0.16). These results are of potential interest during pediatric critical illness, as inflammation is ubiquitous and the effects of multidrug sedation on homeostatic neuroimmune responses need to be considered along with neurodevelopmental effects.

Complement C3 Enhances LPS-Elicited Neuroinflammation and Neurodegeneration Via the Mac1/NOX2 Pathway

Recent studies showed increased expression of complements in various neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. However, the mechanism regulating the expression of complements and their roles in the pathogenesis of neurodegeneration are unclear. We hypothesized that acute neuroinflammation increases the expression and activation of brain complements, which, in turn, participate in chronic neuroinflammation and progressive neurodegeneration. We initially focused on the complement component C3, because C3 can activate microglia by binding to C3 receptors and attaching to damaged neurons destined to be phagocytosed by microglia. We found that complement C3 is upregulated in lipopolysaccharide (LPS)-stimulated neuron/glial cultures. Mechanistic studies revealed that microglia-released proinflammatory factors initiated the enhanced expression of C3 in astroglia during acute neuroinflammation. On the other hand, the sustained C3 expression during chronic neuroinflammation requires releasing damage-associated molecule patterns (DAMPs) from damaged/degenerating brain cells. Our results suggested that DAMPs might act on microglial integrin receptor Mac1 to trigger the activation of NADPH oxidase (NOX2). Activated microglial NOX2 increases the production of extracellular reactive oxygen species (ROS), elevating the levels of intracellular ROS of astroglia and sustaining the astroglial C3 expression. This was supported by the findings showing reduced C3 expression and attenuated neurodegeneration in LPS-treated neuron/glial cultures prepared from mice deficient in Mac1 or NOX2. LPS-induced neurodegeneration and oxidative stress are significantly reduced in C3 KO neuron/glial cultures and mouse brains. Together, this study provides the first evidence demonstrating the role of C3 in regulating chronic neuroinflammation and in driving progressive neurodegeneration.

A single intranasal dose of human mesenchymal stem cell-derived extracellular vesicles after traumatic brain injury eases neurogenesis decline, synapse loss, and BDNF-ERK-CREB signaling.

An optimal intranasal (IN) dose of human mesenchymal stem cell-derived extracellular vesicles (hMSC-EVs), 90 min post-traumatic brain injury (TBI), has been reported to prevent the evolution of acute neuroinflammation into chronic neuroinflammation resulting in the alleviation of long-term cognitive and mood impairments. Since hippocampal neurogenesis decline and synapse loss contribute to TBI-induced long-term cognitive and mood dysfunction, this study investigated whether hMSC-EV treatment after TBI can prevent hippocampal neurogenesis decline and synapse loss in the chronic phase of TBI. C57BL6 mice undergoing unilateral controlled cortical impact injury (CCI) received a single IN administration of different doses of EVs or the vehicle at 90 min post-TBI. Quantifying neurogenesis in the subgranular zone-granule cell layer (SGZ-GCL) through 5'-bromodeoxyuridine and neuron-specific nuclear antigen double labeling at ~2 months post-TBI revealed decreased neurogenesis in TBI mice receiving vehicle. However, in TBI mice receiving EVs (12.8 and 25.6 × 109 EVs), the extent of neurogenesis was matched to naive control levels. A similar trend of decreased neurogenesis was seen when doublecortin-positive newly generated neurons were quantified in the SGZ-GCL at ~3 months post-TBI. The above doses of EVs treatment after TBI also reduced the loss of pre-and post-synaptic marker proteins in the hippocampus and the somatosensory cortex. Moreover, at 48 h post-treatment, brain-derived neurotrophic factor (BDNF), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), and phosphorylated cyclic AMP response-element binding protein (p-CREB) levels were downregulated in TBI mice receiving the vehicle but were closer to naïve control levels in TBI mice receiving above doses of hMSC-EVs. Notably, improved BDNF concentration observed in TBI mice receiving hMSC-EVs in the acute phase was sustained in the chronic phase of TBI. Thus, a single IN dose of hMSC-EVs at 90 min post-TBI can ease TBI-induced declines in the BDNF-ERK-CREB signaling, hippocampal neurogenesis, and synapses.

Lipopolysaccharide (LPS) induced acute lung injury and neuroinflammation in a new mouse model of COVID-19 disease

Objective: Due to their affordability and availability, rodents are the most often employed experimental animals to explore disease mechanisms. Rats and mice's resistance to SARS-CoV-2 infection is impeding a worldwide effort to study the pathogenesis of COVID-19. Our aim was to develop a suitable small animal model of COVID-19 disease to investigate mechanisms of brain and lung inflammation. Methods: Lipopolysaccharide (LPS) was administered intraperitoneally to wildtype (WT) and angiotensin converting enzyme 2 knockout (ACE2KO) mice of the C57BI/6 strain in order to mimic the cytokine storm that results from COVID-19. Since the SARS‐CoV‐2 utilizes human ACE2 as the receptor for entry with subsequent downregulation of ACE2, these mice deficient in ACE2 gene may have a similar mechanism observed in COVID‐19 patients. We selected a minimal dose (500ug/kg) and time period (3h) when several cytokines were elevated to determine the severity of lung injury using a point-counting method on tissue sections stained with hematoxylin and eosin. The data are expressed as a mean percentage of grid points located in the superficial and peribronchial area in up to 20 fields. Congestion, neutrophil infiltration, percentage of peribronchial and superficial intrapulmonary hemorrhage and alveolar space area were all assessed. Results: To see the effect of LPS, WT mice (WT-G) were injected with a minimal dose of LPS (WT LPS-G). We observed a much larger percentage of peribronchial intrapulmonary hemorrhage in WT LPS-G compared to WT-G [(%): WT LPS-G, 12.3±1.8 vs. WT-G, 6.67±1.3; p&lt;0.05; n=5]. Significantly higher percentage of the peribronchial congestion was seen in the LPS group [(%): WT LPS-G, 1.78±0.46 vs. WT-G, 0.770±0.18; p&lt;0.05; n=5]. We implemented this lung histology scoring criteria in ACE2KO mice to see effect of LPS in mice deficient in ACE2 gene. The LPS-injected ACE2KO mice (ACE2KO LPS-G) exhibited a higher percentage of peribronchial intrapulmonary hemorrhage compared to WT-G [(%): ACE2KO LPS-G, 10.6±2.1 vs. WT-G, 6.67±1.3; p&lt;0.05; n=5], peribronchial neutrophil infiltration [(%): ACE2KO LPS-G, 2.50±0.68 vs. WT-G, 0.640±0.54; p&lt;0.05; n=5] and superficial neutrophil infiltration [(%): LPS-G, 2.14±0.59 vs. WT-G, 0.720±0.56; p&lt;0.05; n=5]. These lung pathologies led to 1.6-fold higher lung histopathology scores in the ACE2KO LPS-G compared to WT-G for peribronchial intrapulmonary hemorrhage, 3.9-fold higher scores for peribronchial neutrophil infiltration and 3.0-fold higher scores for superficial neutrophil infiltration. On-going studies are investigating injury in brain since COVID-19 exacerbates brain pathologies. Conclusion: Research on the tissue-specific etiology of the disease will greatly benefit from the creation of this distinctive COVID-19 animal model. This model will facilitate studies investigating diagnostics, prognosis and response to treatments in COVID-19 disease. TL1TR001431 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Implication of the PTN/RPTPβ/ζ Signaling Pathway in Acute Ethanol Neuroinflammation in Both Sexes: A Comparative Study with LPS.

Binge drinking during adolescence increases the risk of alcohol use disorder, possibly by involving alterations of neuroimmune responses. Pleiotrophin (PTN) is a cytokine that inhibits Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ. PTN and MY10, an RPTPβ/ζ pharmacological inhibitor, modulate ethanol behavioral and microglial responses in adult mice. Now, to study the contribution of endogenous PTN and the implication of its receptor RPTPβ/ζ in the neuroinflammatory response in the prefrontal cortex (PFC) after acute ethanol exposure in adolescence, we used MY10 (60 mg/kg) treatment and mice with transgenic PTN overexpression in the brain. Cytokine levels by X-MAP technology and gene expression of neuroinflammatory markers were determined 18 h after ethanol administration (6 g/kg) and compared with determinations performed 18 h after LPS administration (5 g/kg). Our data indicate that Ccl2, Il6, and Tnfa play important roles as mediators of PTN modulatory actions on the effects of ethanol in the adolescent PFC. The data suggest PTN and RPTPβ/ζ as targets to differentially modulate neuroinflammation in different contexts. In this regard, we identified for the first time important sex differences that affect the ability of the PTN/RPTPβ/ζ signaling pathway to modulate ethanol and LPS actions in the adolescent mouse brain.

Regulation of the PD-1/PD-L1 axis in relapsing-remitting Multiple Sclerosis (P2-3.001)

<h3>Objective:</h3> The PD-1/PD-L1 (programmed cell death protein 1/programmed cell death ligand 1) axis plays an important role in the adaptive immune system and has influence on neoplastic and inflammatory diseases. The role of the PD-1/PD-L1 axis in multiple sclerosis (MS) has not yet been investigated in detail. We aimed to delineate distinct expression patterns in peripheral blood mononuclear cell (PBMC) subsets and to evaluate the role of soluble PD-1/PD-L1 in the context of MS. <h3>Background:</h3> PD-L1/PD-1 also exist in soluble forms (sPD-L1/sPD-1) shedded from cellular surfaces. In systemic autoimmune diseases, sPD-1/sPD-L1 serum levels and membrane-bound PD-1/PD-L1 on T and antigen-presenting cells are linked to disease activity and treatment response. In MS, the PD-1/PD-L1 axis and in particular the role of soluble PD-1/PD-L1 is poorly understood but may offer relevance as disease marker and potential target for therapeutic intervention. <h3>Design/Methods:</h3> In depth immunophenotyping by flow cytometry was performed on PBMCs of 49 patients with relapsing-remitting MS (RRMS) and 27 controls. sPD-1/sPD-L1 serum levels were analyzed in a cohort of 84 patients with RRMS and 36 controls. To evaluate the therapeutic potential of soluble PD-L1, 600 μg/kg recombinant protein was systemically administered in Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. <h3>Results:</h3> Patients with RRMS displayed distinct cellular PD-1/PD-L1 expression patterns in PBMCs and an association of sPD-L1 with MS subtype and disease severity. Systemic administration of recombinant PD-L1 in EAE resulted in ameliorated disease severity and reduced infiltration of peripheral immune cells into the CNS. <h3>Conclusions:</h3> The marked expression of PD-1/PD-L1 in immune cell subsets of patients with RRMS, and the correlation of sPD-L1 with disease-severity offers promising potential for the use as a serum marker in the context of MS. Furthermore, enhancement of coregulatory PD-1/PD-L1 signaling by exogenous supplementation of sPD-L1 may serve as a novel therapeutic strategy for severe stages of acute neuroinflammation. <b>Disclosure:</b> Dr. Tsaktanis has nothing to disclose. Mr. Linnerbauer has nothing to disclose. Mrs. Loesslein has nothing to disclose. Prof. Hemmer has received personal compensation in the range of $0-$499 for serving as a Consultant for Vaccitech. Prof. Hemmer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Prof. Hemmer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Polpharma. Prof. Hemmer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Prof. Hemmer has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Allergy Care. The institution of Prof. Hemmer has received research support from Regeneron. The institution of Prof. Hemmer has received research support from German Research Foundation. The institution of Prof. Hemmer has received research support from German Ministry for Education and Research. The institution of Prof. Hemmer has received research support from European Commission. Prof. Hemmer has received intellectual property interests from a discovery or technology relating to health care. Prof. Hemmer has received intellectual property interests from a discovery or technology relating to health care. Mark Mühlau has nothing to disclose. Dr. Quintana has nothing to disclose. Prof. Rothhammer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Prof. Rothhammer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. The institution of Prof. Rothhammer has received research support from German Research Foundation. The institution of Prof. Rothhammer has received research support from European Research Council.

Group 2 innate lymphoid cells resolve neuroinflammation following cerebral ischaemia

BackgroundAcute brain ischaemia elicits pronounced inflammation, which aggravates neural injury. However, the mechanisms governing the resolution of acute neuroinflammation remain poorly understood. In contrast to regulatory T and B cells,...

VCE-005.1, an hypoxia mimetic betulinic acid derivative, induces angiogenesis and shows efficacy in a murine model of traumatic brain injury

One of the main global causes of mortality and morbidity is traumatic brain injury (TBI). Neuroinflammation and brain-blood barrier (BBB) disruption play a pivotal role in the pathogenesis of acute and chronic TBI onset. The activation of the hypoxia pathway is a promising approach for CNS neurodegenerative diseases, including TBI. Herein, we have studied the efficacy of VCE-005.1, a betulinic acid hydroxamate, against acute neuroinflammation in vitro and on a TBI mouse model. The effect of VCE-005.1 on the HIF pathway in endothelial vascular cells was assessed by western blot, gene expression, in vitro angiogenesis, confocal analysis and MTT assays. In vivo angiogenesis was evaluated through a Matrigel plug model and a mouse model of TBI induced by a controlled cortical impact (CCI) was used to assess VCE-005.1 efficacy. VCE-005.1 stabilized HIF-1α through a mechanism that involved AMPK and stimulated the expression of HIF-dependent genes. VCE-005.1 protected vascular endothelial cells under prooxidant and pro-inflammatory conditions by enhancing TJ protein expression and induced angiogenesis both in vitro and in vivo. Furthermore, in CCI model, VCE-005.1 greatly improved locomotor coordination, increased neovascularization and preserved BBB integrity that paralleled with a large reduction of peripheral immune cells infiltration, recovering AMPK expression and reducing apoptosis in neuronal cells. Taken together, our results demonstrate that VCE-005.1 is a multitarget compound that shows anti-inflammatory and neuroprotective effects mainly by preventing BBB disruption and has the potential to be further developed pharmacologically in TBI and maybe other neurological conditions that concur with neuroinflammation and BBB disruption.

Translatome analysis reveals microglia and astrocytes to be distinct regulators of inflammation in the hyperacute and acute phases after stroke.

Neuroinflammation is a hallmark of ischemic stroke, which is a leading cause of death and long-term disability. Understanding the exact cellular signaling pathways that initiate and propagate neuroinflammation after stroke will be critical for developing immunomodulatory stroke therapies. In particular, the precise mechanisms of inflammatory signaling in the clinically relevant hyperacute period, hours after stroke, have not been elucidated. We used the RiboTag technique to obtain microglia and astrocyte-derived mRNA transcripts in a hyperacute (4 h) and acute (3 days) period after stroke, as these two cell types are key modulators of acute neuroinflammation. Microglia initiated a rapid response to stroke at 4 h by adopting an inflammatory profile associated with the recruitment of immune cells. The hyperacute astrocyte profile was marked by stress response genes and transcription factors, such as Fos and Jun, involved in pro-inflammatory pathways such as TNF-α. By 3 days, microglia shift to a proliferative state and astrocytes strengthen their inflammatory response. The astrocyte pro-inflammatory response at 3 days is partially driven by the upregulation of the transcription factors C/EBPβ, Spi1, and Rel, which comprise 25% of upregulated transcription factor-target interactions. Surprisingly, few sex differences across all groups were observed. Expression and log2 fold data for all sequenced genes are available on a user-friendly website for researchers to examine gene changes and generate hypotheses for stroke targets. Taken together, our data comprehensively describe the microglia and astrocyte-specific translatome response in the hyperacute and acute period after stroke and identify pathways critical for initiating neuroinflammation.

Single Atom-Engineered NIR-II Gold Clusters with Ultrahigh Brightness and Stability for Acute Kidney Injury.

Near-infrared-II (NIR-II) imaging has shown great potential for monitoring the pathological progression and deep tissue imaging but is limited to present unmet NIR-II agent. Present fluorophores show a promising prospect for NIR-II imaging, but brightness and photostability are still highly challenging during real-time monitoring. In this work, atom-engineered NIR-II Au24 Cd1 clusters with ultrahigh brightness, stability, and photostability are developed via single atomic Cd doping. Single atom Cd substitutions contribute to Cd 4d state in HOMO and redistribution of energy level near the gap, exhibiting 56-fold fluorescence enhancement of Au24 Cd1 clusters. Meanwhile, single atomic Cd reinforces CdAu bond energy, formation energy, and stabilized cluster structure, leading to persistent stability for up to 1month without decay, as well as excellent photostability of 1h without photobleaching, much longer than clinically approved indocyanine green (<5min). In vivo imaging shows gold clusters can monitor acute kidney injury (AKI) even after 72h of injury, enabling evaluating progression at a very long window. Meanwhile, the bioactive gold clusters can alleviate AKI-induced oxidative stress damage and acute neuroinflammation. Single atom-engineered gold clusters exhibit molecular tracking and diagnostic prospect in kidney-related diseases.

Influenza vaccine is able to prevent neuroinflammation triggered by H7N7 IAV infection.

Influenza A virus (IAV) subtypes are a major cause of illness and mortality worldwide and pose a threat to human health. Although IAV infection is considered a self-limiting respiratory syndrome, an expanded spectrum of cerebral manifestations has been reported following IAV infection. Neurotropic IAVs, such as the H7N7 subtype, are capable of invading the central nervous system (CNS) and replicating in brain cells, resulting in microglia-induced neuroinflammation. Microglial cells, the brain's resident immune cells, are instrumental in the inflammatory response to viral infection. While activation of microglia is important to initially contain the virus, excessive activation of these cells leads to neuronal damage. Previous studies have shown that acute and even long-term IAV-induced neuroinflammation leads to CNS damage. Therefore, the search for possible preventive or therapeutic strategies is of great importance. In this study, we investigated the potential effect of vaccination against acute neuroinflammation induced by H7N7 infection and subsequent neuronal damage in the hippocampus, a particularly vulnerable brain region, comparing young and aged mice. Immunosenescence is one of the striking pathophysiological changes during mammalian aging that leads to "inflammaging" and critically limits the protection by vaccines in the elderly. The results suggest that formalin-inactivated H7N7 vaccine has a preventive effect against the inflammatory responses in the periphery and also in the CNS after H7N7 infection. Cytokine and chemokine levels, increased microglial density, and cell volume after H7N7 infection were all attenuated by vaccination. Further structural analysis of microglial cells also revealed a change in branching complexity after H7N7 infection, most likely reflecting the neuroprotective effect of the vaccination. In addition, synapse loss was prevented in vaccinated mice. Remarkably, engulfment of post-synaptic compartments by microglia can be proposed as the underlying mechanism for spine loss triggered by H7N7 infection, which was partially modulated by vaccination. Although young mice showed better protection against neuroinflammation and the resulting deleterious neuronal effects upon vaccination, a beneficial role of the vaccine was also observed in the brains of older mice. Therefore, vaccination can be proposed as an important strategy to prevent neurological sequelae of H7N7 infection.

ACAT1/SOAT1 Blockade Suppresses LPS-Mediated Neuroinflammation by Modulating the Fate of Toll-like Receptor 4 in Microglia.

Cholesterol is stored as cholesteryl esters by the enzymes acyl-CoA:cholesterol acyltransferases/sterol O:acyltransferases (ACATs/SOATs). ACAT1 blockade (A1B) ameliorates the pro-inflammatory responses of macrophages to lipopolysaccharides (LPS) and cholesterol loading. However, the mediators involved in transmitting the effects of A1B in immune cells is unknown. Microglial Acat1/Soat1 expression is elevated in many neurodegenerative diseases and in acute neuroinflammation. We evaluated LPS-induced neuroinflammation experiments in control vs. myeloid-specific Acat1/Soat1 knockout mice. We also evaluated LPS-induced neuroinflammation in microglial N9 cells with and without pre-treatment with K-604, a selective ACAT1 inhibitor. Biochemical and microscopy assays were used to monitor the fate of Toll-Like Receptor 4 (TLR4), the receptor at the plasma membrane and the endosomal membrane that mediates pro-inflammatory signaling cascades. In the hippocampus and cortex, results revealed that Acat1/Soat1 inactivation in myeloid cell lineage markedly attenuated LPS-induced activation of pro-inflammatory response genes. Studies in microglial N9 cells showed that pre-incubation with K-604 significantly reduced the LPS-induced pro-inflammatory responses. Further studies showed that K-604 decreased the total TLR4 protein content by increasing TLR4 endocytosis, thus enhancing the trafficking of TLR4 to the lysosomes for degradation. We concluded that A1B alters the intracellular fate of TLR4 and suppresses its pro-inflammatory signaling cascade in response to LPS.

Role of the adipocyte immune brain axis in Parkinson's disease: friend or foe?

Role of the adipocyte immune brain axis in Parkinson's disease: friend or foe?

LPS Triggers Acute Neuroinflammation and Parkinsonism Involving NLRP3 Inflammasome Pathway and Mitochondrial CI Dysfunction in the Rat

Whether neuroinflammation leads to dopaminergic nigrostriatal system neurodegeneration is controversial. We addressed this issue by inducing acute neuroinflammation in the substantia nigra (SN) with a single local administration (5 µg/2 µL saline solution) of lipopolysaccharide (LPS). Neuroinflammatory variables were assessed from 48 h to 30 days after the injury by immunostaining for activated microglia (Iba-1 +), neurotoxic A1 astrocytes (C3 + and GFAP +), and active caspase-1. We also evaluated NLRP3 activation and Il-1β levels by western blot and mitochondrial complex I (CI) activity. Fever and sickness behavior was assessed for 24 h, and motor behavior deficits were followed up until day 30. On this day, we evaluated the cellular senescence marker β-galactosidase (β-Gal) in the SN and tyrosine hydroxylase (TH) in the SN and striatum. After LPS injection, Iba-1 (+), C3 (+), and S100A10 (+) cells were maximally present at 48 h and reached basal levels on day 30. NLRP3 activation occurred at 24 h and was followed by a rise of active caspase-1 (+), Il-1β, and decreased mitochondrial CI activity until 48 h. A significant loss of nigral TH (+) cells and striatal terminals was associated with motor deficits on day 30. The remaining TH (+) cells were β-Gal (+), suggesting senescent dopaminergic neurons. All the histopathological changes also appeared on the contralateral side. Our results show that unilaterally LPS-induced neuroinflammation can cause bilateral neurodegeneration of the nigrostriatal dopaminergic system and are relevant for understanding Parkinson's disease (PD) neuropathology.