Search

Preferential energy storage in subcutaneous adipose tissue (SAT) confers protection against obesity-induced pathophysiology in females. Females also exhibit distinct immunological responses, relative to males. These differences are often attributed to sex hormones, but reciprocal interactions between metabolism, immunity, and gonadal steroids remain poorly understood. Here, we systematically characterized adipose tissue hypertrophy, sex steroids, and inflammation in male and female mice after increasing durations of high-fat diet (HFD)-induced obesity. After observing that sex differences in adipose tissue distribution before HFD were correlated with lasting protection against inflammation in females, we hypothesized that a priori differences in the ratio of subcutaneous to visceral fat might mediate this relationship. To test this, male and female mice received SAT lipectomy (LPX) or sham surgery before HFD challenge, followed by analysis of glial reactivity, adipose tissue inflammation, and reproductive steroids. Because LPX eliminated female resistance to the pro-inflammatory effects of HFD without changing circulating sex hormones, we conclude that sexually dimorphic organization of subcutaneous and visceral fat determines susceptibility to inflammation in obesity.

Chronic stress is a major risk factor in the pathophysiology of many neuropsychiatric disorders. Further, chronic stress conditions can promote neuroinflammation and inflammatory responses in both humans and animal models. Type I interferons (IFN-I) are critical mediators of the inflammatory response in the periphery and responsible for the altered mood and behavior. However, the underlying mechanisms are not well understood. In the present study, we investigated the role of IFN-I signaling in chronic stress-induced changes in neuroinflammation and behavior. Using the chronic restraint stress model, we found that chronic stress induces a significant increase in serum IFNβ levels in mice, and systemic blockade of IFN-I signaling attenuated chronic stress-induced infiltration of macrophages into prefrontal cortex and behavioral abnormalities. Furthermore, complement component 3 (C3) mediates systemic IFNβ-induced changes in neuroinflammation and behavior. Also, we found significant increases in the mRNA expression levels of IFN-I stimulated genes in the prefrontal cortex of depressed suicide subjects and significant correlation with C3 and inflammatory markers. Together, these findings from animal and human postmortem brain studies identify a crucial role of C3 in IFN-I-mediated changes in neuroinflammation and behavior under chronic stress conditions.

Spontaneous Intracerebral hemorrhage (ICH) is a devastating injury that accounts for 10–15% of all strokes. The rupture of cerebral blood vessels damaged by hypertension or cerebral amyloid angiopathy creates a space-occupying hematoma that contributes toward neurological deterioration and high patient morbidity and mortality. Numerous protocols have explored a role for surgical decompression of ICH via craniotomy, stereotactic guided endoscopy, and minimally invasive catheter/tube evacuation. Studies including, but not limited to, STICH, STICH-II, MISTIE, MISTIE-II, MISTIE-III, ENRICH, and ICES have all shown that, in certain limited patient populations, evacuation can be done safely and mortality can be decreased, but functional outcomes remain statistically no different compared to medical management alone. Only 10–15% of patients with ICH are surgical candidates based on clot location, medical comorbidities, and limitations regarding early surgical intervention. To date, no clearly effective treatment options are available to improve ICH outcomes, leaving medical and supportive management as the standard of care. We recently identified that remote ischemic conditioning (RIC), the non-invasive, repetitive inflation-deflation of a blood pressure cuff on a limb, non-invasively enhanced hematoma resolution and improved neurological outcomes via anti-inflammatory macrophage polarization in pre-clinical ICH models. Herein, we propose a pilot, placebo-controlled, open-label, randomized trial to test the hypothesis that RIC accelerates hematoma resorption and improves outcomes in ICH patients. Twenty ICH patients will be randomized to receive either mock conditioning or unilateral arm RIC (4 cycles × 5 min inflation/5 min deflation per cycle) beginning within 48 h of stroke onset and continuing twice daily for one week. All patients will receive standard medical care according to latest guidelines. The primary outcome will be the safety evaluation of unilateral RIC in ICH patients. Secondary outcomes will include hematoma volume/clot resorption rate and functional outcomes, as assessed by the modified Rankin Scale (mRS) at 1- and 3-months post-ICH. Additionally, blood will be collected for exploratory genomic analysis. This study will establish the feasibility and safety of RIC in acute ICH patients, providing a foundation for a larger, multi-center clinical trial.

BackgroundEPS8 is a scaffolding protein that regulates proliferation, actin dynamics and receptor trafficking. Its expression is increased in cancer, enhancing mitogenesis, migration and tumorigenesis. Src phosphorylates EPS8 at four tyrosine residues, although the function is unknown. Here we investigated the pro-oncogenic role of EPS8 tyrosine phosphorylation at Src target sites in HNSCC.MethodsPlasmids expressing EPS8 Src-mediated phosphorylation site mutants (Y485F, Y525F, Y602F, Y774F and all four combined [FFFF]) were expressed in cells containing a normal endogenous level of EPS8. In addition, cells were treated with dasatinib to inhibit Src activity. EPS8 downstream targets were evaluated by western blotting. Wound closure, proliferation, immunofluorescence and tumorgenicity assays were used to investigate the impact of phenylalanine mutations on EPS8 biological functions.ResultsFOXM1, AURKA, and AURKB were decreased in cells expressing FFFF- and Y602F-EPS8 mutants, while cells harbouring the Y485F-, Y525F- and Y774F-EPS8 mutants showed no differences compared to controls. Consistent with this, dasatinib decreased the expression of EPS8 targets. Moreover, Y602F- and FFFF-EPS8 mutants reduced mitogenesis and motility. Strikingly though, FFFF- or Y602F-EPS8 mutants actually promoted tumorigenicity compared with control cells.ConclusionsPhosphorylation of EPS8 at Y602 is crucial for signalling to the cell cycle and may provide insight to explain reduced efficacy of dasatinib treatment.

Induction of the inflammasome protein cryopyrin (NLRP3) in visceral adipose tissue (VAT) promotes release of the proinflammatory cytokine IL-1β in obesity. Although this mechanism contributes to peripheral metabolic dysfunction, effects on the brain remain unexplored. We investigated whether visceral adipose NLRP3 impairs cognition by activating microglial IL-1 receptor 1 (IL-1R1). After observing protection against obesity-induced neuroinflammation and cognitive impairment in NLRP3-KO mice, we transplanted VAT from obese WT or NLRP3-KO donors into lean recipient mice. Transplantation of VAT from a WT donor (TRANS(WT)) increased hippocampal IL-1β and impaired cognition, but VAT transplants from comparably obese NLRP3-KO donors (TRANS(KO)) had no effect. Visceral adipose NLRP3 was required for deficits in long-term potentiation (LTP) in transplant recipients, and LTP impairment in TRANS(WT) mice was IL-1 dependent. Flow cytometric and gene expression analyses revealed that VAT transplantation recapitulated the effects of obesity on microglial activation and IL-1β gene expression, and visualization of hippocampal microglia revealed similar effects in vivo. Inducible ablation of IL-1R1 in CX3CR1-expressing cells eliminated cognitive impairment in mice with dietary obesity and in transplant recipients and restored immunoquiescence in hippocampal microglia. These results indicate that visceral adipose NLRP3 impairs memory via IL-1–mediated microglial activation and suggest that NLRP3/IL-1β signaling may underlie correlations between visceral adiposity and cognitive impairment in humans.

BackgroundAcute respiratory distress syndrome (ARDS) is a life-threatening clinical syndrome whose potential to become one of the most grievous challenges of the healthcare system evidenced by the COVID-19 pandemic. Considering the lack of target-specific treatment for ARDS, it is absolutely exigent to have an effective therapeutic modality to reduce hospitalization and mortality rate as well as to improve quality of life and outcomes for ARDS patients. ARDS is a systemic inflammatory disease starting with the pulmonary system and involves all other organs in a morbid bidirectional fashion. Mounting evidence including our findings supporting the notion that cannabinoids have potential to be targeted as regulatory therapeutic modalities in the treatment of inflammatory diseases. Therefore, it is plausible to test their capabilities as alternative therapies in the treatment of ARDS. In this study, we investigated the potential protective effects of cannabichromene (CBC) in an experimental model of ARDS.MethodsWe used, for the first time, an inhalant CBC treatment as a potential therapeutic target in a murine model of ARDS-like symptoms. ARDS was induced by intranasal administration of Poly(I:C), a synthetic mismatched double-stranded RNA, into the C57BL/6 mice (6–10 male mice/group, including sham, placebo, and CBC treated), three once-daily doses followed by a daily dose of inhalant CBC or placebo for the period of 8 days starting the first dose 2 h after the second Poly(I:C) treatment. We employed histologic, immunohistochemistry, and flow cytometry methods to assess the findings. Statistical analysis was performed by using one way analysis of variance (ANOVA) followed by Newman–Keuls post hoc test to determine the differences among the means of all experimental groups and to establish significance (p< 0.05) among all groups.ResultsOur data showed that CBC was able to reverse the hypoxia (increasing blood O2saturation by 8%), ameliorate the symptoms of ARDS (reducing the pro-inflammatory cytokines by 50% in lung and blood), and protect the lung tissues from further destruction. Further analysis showed that CBC may wield its protective effects through transient receptor potential (TRP) cation channels, TRPA1 and TRPV1, increasing their expression by 5-folds in lung tissues compared to sham and untreated mice, re-establishing the homeostasis and immune balance.ConclusionOur findings suggest that inhalant CBC may be an effective alternative therapeutic target in the treatment of ARDS. In addition, Increased expression of TRPs cation channels after CBC treatment proposes a novel role for TRPs (TRPA1 and TRPV2) as new potential mechanism to interpret the beneficial effects of CBC as well as other cannabinoids in the treatment of ARDS as well as other inflammatory diseases. Importantly, delivering CBC through an inhaler device is a translational model supporting the feasibility of trial with human subjects, authorizing further research.

Elabela is an endogenous secreted peptide and its role has been investigated in heart and preeclampsia development. Endogenous peptides are usually known for their potential role as regulators of the innate immune function. In this study, we evaluated the expression of Elabela by the three different types of Innate Lymphoid Cells (ILCs): ILC1s, ILC2s, and ILC3s. ILCs are a family of immune cells that mirror the phenotypes and functions of T cells and promptly response to signals from injured tissues. We hypothesized that ILCs may regulate the immune response by expressing Elabela (ILCsEla+). Since heart and the uterine decidua have been the focus of studies about Elabela, we collected both tissues from ICR males (n=3), virgins (n=3), and pregnant females on the 6 th (n=3), 10 th (n=3), and 14 th (n=3) gestation days. The collected tissues were prepared for further flow cytometric analysis. Also, part of the decidua from 10 th gestation day was used to perform Mixed Lymphocyte Reaction (MLR) in vitro . Our findings showed that ILCs in both heart and decidua express Elabela. The analysis showed that the number of ILC3sEla+ (10.7 + 1.2) was higher in virgin female comparing to males (3.3 + 0.8) (p=0.0032). In pregnant females, the total number of ILCsEla+ increased during the period of 6 th to 14 th gestation days in both heart {6 th (27 + 1.1); 14 th (42 + 1.5) (p=0.0104)} and decidua {6 th (26.6 + 0.5); 14 th (47 + 12) (p= 0.0273)} . The analysis of the MLR showed that Elabela was able to decrease the total number of active T cells. In conclusion, our study showed that Elabela as part of the innate immune system is expressed by ILCs. Also, there is a sex difference in the number of ILCsEla+ in the heart. These findings highlight the importance of exploring the role of Elabela as an immunomodulator in different cardiovascular disease models.

There is a dire need for due innovative therapeutic modalities to improve outcomes of AD patients. In this study, we tested whether cannabidiol (CBD) improves outcomes in a translational model of familial AD and to investigate if CBD regulates interleukin (IL)-33 and triggering receptor expressed on myeloid cells 2 (TREM2), which are associated with improved cognitive function. CBD was administered to 5xFAD mice, which recapitulate early onset, familial AD. Behavioral tests and immunoassays were used to evaluate cognitive and motor outcomes. Our findings suggest that CBD treatment enhanced IL-33 and TREM2 expression, ameliorated the symptoms of AD, and retarded cognitive decline.

The coronavirus disease-19 (COVID-19) pandemic is an unprecedented worldwide health crisis. COVID-19 is caused by SARS-CoV-2, a highly infectious pathogen that is genetically similar to SARS-CoV. Similar to other recent coronavirus outbreaks, including SARS and MERS, SARS-CoV-2 infected patients typically present with fever, dry cough, fatigue, and lower respiratory system dysfunction, including high rates of pneumonia and acute respiratory distress syndrome (ARDS); however, a rapidly accumulating set of clinical studies revealed atypical symptoms of COVID-19 that involve neurological signs, including headaches, anosmia, nausea, dysgeusia, damage to respiratory centers, and cerebral infarction. These unexpected findings may provide important clues regarding the pathological sequela of SARS-CoV-2 infection. Moreover, no efficacious therapies or vaccines are currently available, complicating the clinical management of COVID-19 patients and emphasizing the public health need for controlled, hypothesis-driven experimental studies to provide a framework for therapeutic development. In this mini-review, we summarize the current body of literature regarding the central nervous system (CNS) effects of SARS-CoV-2 and discuss several potential targets for therapeutic development to reduce neurological consequences in COVID-19 patients.

Formation of neutrophil extracellular traps worsens cerebrovascular outcomes after traumatic brain injury., Traumatic brain injury (TBI) is a major cause of mortality and morbidity. Preventative measures reduce injury incidence and/or severity, yet one-third of hospitalized patients with TBI die from secondary pathological processes that develop during supervised care. Neutrophils, which orchestrate innate immune responses, worsen TBI outcomes via undefined mechanisms. We hypothesized that formation of neutrophil extracellular traps (NETs), a purported mechanism of microbial trapping, exacerbates acute neurological injury after TBI. NET formation coincided with cerebral hypoperfusion and tissue hypoxia after experimental TBI, while elevated circulating NETs correlated with reduced serum deoxyribonuclease-1 (DNase-I) activity in patients with TBI. Functionally, Toll-like receptor 4 (TLR4) and the downstream kinase peptidylarginine deiminase 4 (PAD4) mediated NET formation and cerebrovascular dysfunction after TBI. Last, recombinant human DNase-I degraded NETs and improved neurological function. Thus, therapeutically targeting NETs may provide a mechanistically innovative approach to improve TBI outcomes without the associated risks of global neutrophil depletion.

Cannabis-inspired medical products are garnering increasing attention from the scientific community, general public, and health policy makers. A plethora of scientific literature demonstrates intricate engagement of the endocannabinoid system with human immunology, psychology, developmental processes, neuronal plasticity, signal transduction, and metabolic regulation. Despite the therapeutic potential, the adverse psychoactive effects and historical stigma, cannabinoids have limited widespread clinical application. Therefore, it is plausible to weigh carefully the beneficial effects of cannabinoids against the potential adverse impacts for every individual. This is where the concept of “personalized medicine” as a promising approach for disease prediction and prevention may take into the account. The goal of this review is to provide an outline of the endocannabinoid system, including endocannabinoid metabolizing pathways, and will progress to a more in-depth discussion of the therapeutic interventions by endocannabinoids in various neurological disorders.

Aging is a complex phenomenon associated with a wide spectrum of physical and physiological changes affecting every part of all metazoans, if they escape death prior to reaching maturity. Critical to survival, the immune system evolved as the principal component of response to injury and defense against pathogen invasions. Because how significantly immune system affects and is affected by aging, several neologisms now appear to encapsulate these reciprocal relationships, such as Immunosenescence. The central part of Immunosenescence is Inflammaging –a sustained, low-grade, sterile inflammation occurring after reaching reproductive prime. Once initiated, the impact of Inflammaging and its adverse effects determine the direction and magnitudes of further Inflammaging. In this article, we review the nature of this vicious cycle, we will propose that phytocannabinoids as immune regulators may possess the potential as effective adjunctive therapies to slow and, in certain cases, reverse the pathologic senescence to permit a more healthy aging.

Background and Purpose: There is presently no specific therapy for the treatment of VCID. We reported that daily C-RIC (4mo) is effective in young mice by improving cerebral blood flow (CBF), minimizing white matter (WM) damage and improving functional outcomes in Bilateral Carotid Artery Stenosis model (BCAS.) The purpose of this study was to evaluate whether 4 months (4 MO-C-RIC) is effective in male and female aged mouse and if the treatment effects are durable out to 6MOS. Methods: Microcoil induced BCAS model was used to induce chronic hypoperfusion. Adult C57BL/6 both male & female mice (14-months ) were randomly assigned to 3-different groups (N=10), and subjected to Sham, BCAS+sham RIC, BCAS+RIC. C-RIC was started 7d post-surgery daily for 4MOs. Behavioral test and CBF was performed at 1, 4 and 6MO after BCAS and Sham surgery. Functional outcomes were assessed using novel object recognition (NOR) test for non-spatial working memory, and hanging wire and beam walk test for motor/muscular impairment. Histopathology as well as immunohistochemistry for CD31/α-SMA; GFAP, myelin basic protein (MBP) and beta-amyloid were also performed on the brain tissue collected after the neurobehavioral tests. Results: C-RIC-therapy for 4MO significantly improved CBF in the male and female BCAS+C-RIC groups at all time points compared to BCAS-Sham RIC groups. Mice from the BCAS group +Sham C-RIC group showed significant loss in the discrimination index as determined by the NOR test, and poor motor function in hanging wire and beam walk test. C-RIC- significantly improved these functional outcomes. Histopathology showed prevention of WM degeneration and myelin basic protein by C-RIC. Immunohistochemical analysis at 6 MOs showed increased CD31 (angiogenesis) and a-SMA staining (arteriogenesis) indicating collateral remodeling in the C-RIC group compared to BCAS-sham RIC. Conclusions: Daily 4MO C-RIC-therapy improves long term CBF and vascular architecture at 6 MO and reduces WM damage and improves functional outcomes in aged males and females C-RIC induces durable long term collateral remodeling. C-RIC is a promising therapy for VCID and is ready for future clinical trials in VCID.

The CNS is regarded as an immunoprivileged organ, evading routine immune surveillance; however, the coordinated development of immune responses profoundly influences outcomes after brain injury. Innate lymphoid cells (ILCs) are cytokine-producing cells that are critical for the initiation, modulation, and resolution of inflammation, but the functional relevance and mechanistic regulation of ILCs are unexplored after acute brain injury. We demonstrate increased proliferation of all ILC subtypes within the meninges for up to 1 year after experimental traumatic brain injury (TBI) while ILCs were present within resected dura and elevated within cerebrospinal fluid (CSF) of moderate-to-severe TBI patients. In line with energetic derangements after TBI, inhibition of the metabolic regulator, AMPK, increased meningeal ILC expansion, whereas AMPK activation suppressed proinflammatory ILC1/ILC3 and increased the frequency of IL-10-expressing ILC2 after TBI. Moreover, intracisternal administration of IL-33 activated AMPK, expanded ILC2, and suppressed ILC1 and ILC3 within the meninges of WT and Rag1-/- mice, but not Rag1-/- IL2rg-/- mice. Taken together, we identify AMPK as a brake on the expansion of proinflammatory, CNS-resident ILCs after brain injury. These findings establish a mechanistic framework whereby immunometabolic modulation of ILCs may direct the specificity, timing, and magnitude of cerebral immunity.

Hallmark features of acute kidney injury (AKI) include mobilization of immune and inflammatory mechanisms culminating in tissue injury. Emerging information indicates heterogeneity of neutrophils with pro- and anti-inflammatory functions (N1 and N2, respectively). Also, regulatory T-17 (Treg17) cells curtail T helper 17 (Th-17)-mediated proinflammatory responses. However, the status of Treg17 cells and neutrophil phenotypes in AKI are not established. Furthermore, cannabidiol exerts immunoregulatory effects, but its impact on Treg17 cells and neutrophil subtypes is not established. Thus, we examined the status of Treg17 cells and neutrophil subtypes in AKI and determined whether cannabidiol favors regulatory neutrophils and T cells accompanied with renoprotection. Accordingly, mice were subjected to bilateral renal ischemia-reperfusion injury (IRI), without or with cannabidiol treatment; thereafter, kidneys were processed for flow cytometry analyses. Renal IRI increased N1 and Th-17 but reduced N2 and Treg17 cells accompanied with disruption of mitochondrial membrane potential (ψm) and increased apoptosis/necrosis and kidney injury molecule-1 (KIM-1) immunostaining compared with their sham controls. Importantly, cannabidiol treatment preserved ψm and reduced cell death and KIM-1 accompanied by restoration of N1 and N2 imbalance and preservation of Treg17 cells while decreasing Th-17 cells. The ability of cannabidiol to favor development of Treg17 cells was further established using functional mixed lymphocytic reaction. Subsequent studies showed higher renal blood flow and reduced serum creatinine in cannabidiol-treated IRI animals. Collectively, our novel observations establish that renal IRI causes neutrophil polarization in favor of N1 and also reduces Treg17 cells in favor of Th-17, effects that are reversed by cannabidiol treatment accompanied with significant renoprotection.

Neuroinflammation remains a central piece in Parkinson's disease (PD) pathophysiology. However, mechanisms by which PD links to the neuroinflammation remain elusive. Here, for the first time, we report that lower dose of niacin in PD patients may affect macrophage polarization from M1 (pro-inflammatory) to M2 (counter-inflammatory) profile through the niacin receptor GPR109A. Skew in the peripheral macrophages were accompanied by improved quality of life assessments in patients. Low dose niacin supplementation may be beneficial in PD, boosting anti-inflammatory processes and suppressing inflammation. Varied niacin dosages for longer durations may further reveal the potential role of anti-inflammatory interventions in PD progression.