Increasing evidence suggests antidepressants possess neuroprotective and anti-inflammatory properties. Hypidone hydrochloride (YL-0919), a novel antidepressant with rapid antidepressant effects currently in Phase II clinical trials, exhibits antidepressant, anxiolytic, and cognitive-enhancing activities, but its potential role in Parkinson’s disease (PD)-related neuronal damage remains unexplored. Here, we investigated the effects of YL-0919 on an MPTP-induced PD mouse model and on MPP+-induced neuronal damage model. This study demonstrated that YL-0919 ameliorated PD pathology in mice, as evidenced by reduced symptom severity, attenuated inflammatory response, diminished neuronal damage, and improved motor dysfunction. Furthermore, YL-0919 reduced ferroptosis in MPP+-induced SH-SY5Y and PC12 cells by reduced Fe2+ staining, intracellular ROS, lipid peroxidation levels, and mitochondrial membrane potential. Mechanistically, YL-0919 inhibited neuronal ferroptosis by regulating the Sigma1R-PI3K-AKT-ACSL4 axis, thereby alleviating neurological impairment. These findings reveal a novel neuroprotective mechanism of YL-0919 in PD, highlighting the Sigma1R-PI3K-AKT-ACSL4 axis as a promising therapeutic target for mitigating PD symptoms through ferroptosis inhibition.

Exercise has been shown to alleviate depressive symptoms and enhance bodily functions. However, the precise mechanisms underlying its antidepressant effects remain incompletely understood. In this study, we observed that treadmill exercise may exert antidepressant effects in a chronic restraint stress (CRS) mouse model by modulating the proinflammatory Growth Differentiation Factor 15 (GDF15)-extracellular signal-regulated kinase (ERK) signaling pathway. Treadmill exercise improved cognitive behaviors in CRS mice and alleviated neuroinflammation, as evidenced by decreased expression of TNF-α, IL-1β, IL-6, and attenuated microglia activation. Intriguingly, we found that treadmill exercise inhibited the expression of GDF15, a biomarker associated with many immune disorders, which is increased following CRS. Mechanistically, treadmill exercise may attenuate neuroinflammation by suppressing GDF15-induced ERK activation. We thus identified a novel mechanism by which treadmill exercise attenuates depression. Modulation of the GDF15-ERK pathway may have therapeutic implications for depression.

BACKGROUND:Anxiety disorder is a highly prevalent mental health issue globally; however, existing therapeutic approaches have limitations such as significant side effects and poor compliance. Vagus nerve stimulation (VNS) has been used to treat emotional distress, while the underlying mechanisms remain elusive. METHODS:A chronic restraint stress (CRS)-induced mouse anxiety model in vivo and a corticosterone (CORT)-induced neuronal cell death model in vitro were employed, followed by treatment with vagus nerve stimulation and α7nAChR agonists or antagonists. Anxiety levels were assessed using the open field test (OFT), elevated plus maze (EPM), and novelty-suppressed feeding test (NSFT). Histopathological staining and immunofluorescence staining were performed to detect the pathological changes of neuronal injury in anxiety disorders. Western blot was conducted to measure the protein expression levels of GPX4, SLC7A11, and ACSL4. Enzyme-linked immunosorbent assay (ELISA) was used to measure the expression levels of anxiety-related pro-inflammatory cytokines, while quantitative real-time polymerase chain reaction (qPCR) was employed to detect the mRNA expression levels of GPX4, SLC7A11, and ACSL4. RESULTS:In this study, we found that VNS significantly alleviated anxiety-like behaviors, reduced hippocampal ferroptosis-related damage and inflammatory responses in anxiety mice. α7nAChR antagonist abolished VNS-mediated protective effects against ferroptosis-related neuronal damage and anxiety, while α7nAChR agonists produced similar anxiolytic effects to VNS. Mechanistically, VNS activated α7nAChR signaling, thereby upregulating the expression of GPX4 and SLC7A11, inhibiting ACSL4-mediated lipid peroxidation, and ultimately suppressing anxiety-induced ferroptosis-related neuronal damage. CONCLUSION:This study reveals a novel mechanism underlying the anxiolytic effect of VNS, that is, by activating α7nAChR signal, VNS inhibits CRS-induced ferroptosis-related neural damage. Our findings provide new insights into mechanism of anxiety disorders and lay a theoretical foundation for the clinical application of VNS.

Objective T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3), a critical regulator of innate and adaptive immune responses, has been considered as a promising new target for immunotherapy. Based on an existing laboratory murine-derived anti-human Tim-3 antibody, this study aims to employ computer-aided molecular design to construct a mammalian cell-displayed antibody library targeting human Tim-3 and to screen for antibodies with optimized function. Methods The parental Tim-3 sequence was designed and optimized via a computer-assisted molecular model construction platform and mammalian cell-displayed antibody library technology. The plasmid library encoding the Tim-3-targeted mammalian antibody library was obtained by molecular biology techniques including Overlap PCR, vector cleavage, enzyme ligation and transformation. Novel antibody sequences were identified through sequencing alignment, followed by ELISA-based screening to isolate high-expression and high-affinity candidates. The function of the optimized antibody was further verified by in vitro assays (RT-PCR and CCK-8). Results Utilizing computer-aided design platform, five key amino acid substitutions were designed and introduced into the light and heavy chains of the parental murine-derived anti-human Tim-3 antibody. Three mutant light chains (L-1, L-2 and L-3) and heavy chains (H-1, H-2 and H-3) were successfully generated by Overlap PCR. Subsequent ligation into vectors and transformation into TOP10 electrocompetent cells yielded a plasmid library with substantial sequence diversity. Sequence analysis and purification of new antibodies resulted in the identification of an antibody with higher affinity, named No.1. RT-PCR showed that after blockade with antibody No.1, transcription levels of IFN-β, TNF-α, IL-1β and IL-6 were significantly upregulated in the macrophage cell line RAW264.7 cells and microglia cell line BV2 cells, and a similar upregulation was observed in levels of IL-2 and IFN-γ in JurkatTim-3-high cells. In these assays, antibody No.1 exhibited greater blocking efficacy than the parental Tim-3 antibody. CCK-8 assays demonstrated that antibody No.1 promoted JurkatTim-3-high cells proliferation more effectively than the parental Tim-3 antibody. Conclusion A novel humanized Tim-3 antibody (No.1) with enhanced affinity and capacity to upregulate multiple cytokine expressions in both human and murine cell lines was obtained via a computer-aided molecular design platform and mammalian cell antibody display library technology.

INTRODUCTION:Epilepsy affects more than 70 million individuals worldwide, contributing to early mortality, disability, and cognitive impairment. Antidepressants have been explored for epilepsy treatment, although their effects and underlying mechanisms remain unclear. Ferroptosis has been implicated in numerous neurological disorders, including epilepsy, but the regulatory mechanisms behind neuronal damage caused by epilepsy remain unclear. OBJECTIVES:This study aimed to investigate the effect of fluoxetine (FLX) on epilepsy and the underlying mechanisms. METHODS:We established a mouse model of epilepsy induced by kainic acid (KA) to evaluate the effects of the antidepressant FLX on seizure activity in mice, as well as its impact on neural damage and cognitive function. We also clarified the effects of FLX on epilepsy-related neuronal ferroptosis in both the epilepsy mouse model and the glutamate-induced cell death model. The key E3 ligases, key signaling pathways and receptors by which FLX regulates the ubiquitination of GPX4, a crucial ferroptosis regulator, were further investigated. Additionally, we characterized the lysine residue sites and polyubiquitination patterns that participate in the ubiquitination of GPX4. RESULTS:This study demonstrates that FLX provides neuroprotective and cognitive benefits in murine epilepsy models by inhibiting neuronal ferroptosis. FLX stabilizes glutathione peroxidase 4 (GPX4), a ferroptosis regulator, by preventing its ubiquitination and proteasomal degradation. The antiferroptotic effect of FLX is mediated by the Sigma-1 receptor (Sigma1R), as its inhibition reverses the protective effects of FLX on epilepsy and GPX4 stability. In neurons, the FLX/Sigma1R axis suppresses the JNK/p38 MAPK-mediated upregulation of MDM2, an E3 ubiquitin ligase, thereby disrupting MDM2-induced K48-linked polyubiquitination of GPX4 at Lys162 and Lys167. This enhances GPX4 stability and increases antioxidant defenses. CONCLUSIONS:These findings reveal a novel molecular pathway (Sigma1R-JNK/p38 MAPK-MDM2-GPX4 axis) through which FLX inhibits ferroptosis, highlighting its therapeutic potential for epilepsy and other ferroptosis-related neurological disorders.

Major depressive disorder (MDD) is a leading cause of disability and disease burden worldwide, and increasing attention has been paid to the role of immune dysregulation in MDD pathogenesis. However, the key cellular subsets, hub molecules, and their regulatory mechanisms have not yet been fully elucidated. This study investigated the roles of Sigma-1 receptor (Sigma-1R) and CD36 in myeloid cells, exploring their potential as targets for modulating peripheral inflammation in MDD. We performed a random-effects meta-analysis of five public PBMC transcriptomic cohorts (n = 1388) and analyzed a public PBMC scRNA-seq dataset (MDD, n = 8; HC, n = 8) to characterize cell-type specific expression patterns. CRS mouse experiments and complementary in vitro assays were conducted to examine Sigma-1R regulation of CD36 and the role of the E3 ligase TRIM28, using pharmacological agonism (Hypidone hydrochloride, YL-0919 or SA4503) and antagonism (BD-1047), flow cytometry, cytokine measurements, co-immunoprecipitation, and ubiquitination/proteasome-degradation assays. The meta-analysis estimated a small, non-significant pooled difference in CD36 expression in bulk PBMC between the MDD and HC groups (SMD = 0.043, 95

IntroductionMusic has been widely used for disease intervention, while the underlying mechanisms remain to be determined. This study explored whether our novel music combination, which is composed of four pieces of music, can promote neuroimmune homeostasis and then relieve stress.MethodsFifty-five participants were enrolled in the study, and they underwent three separate music therapy sessions or periods of rest. Saliva and blood samples were collected, cognitive task testing was conducted, and electrocardiographic (ECG) data were recorded.ResultsThe results showed that our new music combination increased the heart rate variability (HRV) index [RMSSD, PNN20, PNN50, and high-frequency (HF)/NU] while decreasing LF/NU, which suggested restoration of balance between the sympathetic and parasympathetic activity and relieved stress. In addition, participants in the music group had lower Balloon Analogue Risk Task (BART) test results and higher Multiple Object Tracking (MOT) task test results, suggesting increased attention and stress relief. Music therapy also increased the IgA while decreasing cortisol concentrations.DiscussionThis study reveals that our novel music combination may relieve stress by promoting neuroimmune homeostasis, which sheds new light on the mechanisms of music therapy and suggests new approaches for intervention.

Background Calcitonin gene-related peptide (CGRP), a 37-amino-acid neuropeptide, is widely distributed in the central and peripheral nervous systems and participates in regulating various physiological and pathological processes such as vasodilation, inflammation, and pain. Recent studies have shown that CGRP also exhibits neuroprotective effects, however, its role in epileptic neuronal damage remains unclear. Methods We conducted experiments on kainic acid (KA)-induced epileptic mice in vivo and glutamate induced neuronal cell death models in vitro, with treatments of CGRP and agonists or inhibitors of the corresponding receptors and pathway proteins. Cognitive function was evaluated by open-field task, novel object recognition test, and morris water maze test. Histopathological staining and immunofluorescence staining were used to detect the pathological damage of epileptic neuronal damage. The expression of P2RX7 and JAK1-STAT1 pathway were measured by western blots. Proinflammatory cytokines associated with epilepsy were detected by qPCR. Results CGRP alleviated epilepsy in mice, characterized by a reduction in the frequency and grade of epileptic seizures, attenuated inflammatory response, decreased neuronal damage, and improved cognitive and behavioral abilities. When the underlying mechanisms were investigated, we found that P2RX7 plays a key role in the pathogenesis of neuronal damage. CGRP inhibited the expression of P2RX7, thus inhibited neuronal death, resulting in downregulation of epileptic seizures. In addition, JAK1-STAT1 pathway was identified as a pivotal pathway that can be engaged by CGRP to inhibit P2RX7 in epilepsy. Conclusions These results provide new insights into the mechanisms of neuroprotection mediated by the neuropeptide CGRP. Moreover, targeting the JAK1/STAT1/P2RX7 pathway is a promising strategy for the treatment of epilepsy.

BACKGROUND:Obstructive sleep apnea (OSA) is characterized as a low-grade inflammatory condition resulting from injury induced by intermittent hypoxia (IH). Interleukin-22 (IL-22), a mucosa-targeting cytokine, regulates tight junction proteins like Claudin-4 (CLDN4) to enhance barrier function, yet its role in OSA remains underexplored. METHODS:This pilot observational study included consecutive patients who underwent polysomnography. Plasma IL-22 and CLDN4 levels were measured using an enzyme-linked immunosorbent assay. Rat models of IH-exposed colon tissues were used for histology and immunohistochemical analysis. All statistical analyses were performed using SPSS 20.0. RESULTS:The expression of plasma IL-22 and CLDN4 was found to be positively correlated in OSA patients (r = 0.512, p < 0.001). Plasma IL-22 and CLDN4 levels exhibited a significant positive correlation with the apnea-hypopnea index (both p < 0.001), arousal index (p = 0.001 and p = 0.014), oxygen desaturation index (p < 0.001 and p = 0.001), and T90 (r = 0.379, p < 0.001 and p = 0.002). They also exhibited significant negative correlations with sleep efficiency (0.029; p = 0.004), REM sleep phases (p = 0.037 and p = 0.015), and mean oxygen saturation (SpO2) (p = 0.044 and p = 0.006). Plasma IL-22 and CLDN4 were significantly increased in the OSA group (p < 0.001), especially in severe OSA. The diagnostic value of plasma IL-22 combined with CLDN4 was superior to that of other indicators, with an AUC of 0.849 (0.783-0.915) for diagnosing OSA and an AUC of 0.909 (0.856-0.961) for diagnosing severe OSA. Pathological staining of the rat colon confirmed the damage of intermittent hypoxia (IH) to the intestine. The rat IH group had more IL-22 in the intestinal lymph node and more CLDN4 in the intestinal epithelium than the normal control (NC) group. The expression trends of IL-22 and CLDN4 in rat plasma were consistent with those observed in tissue samples. CONCLUSION:Plasma IL-22 and CLDN4 were associated with OSA severity and mucosal barrier alterations. Their co-regulation aligns with preclinical models of IH-driven barrier adaptation, supporting further mechanistic investigation. The diagnostic potential of the IL-22 +CLDN4 panel warrants validation in larger patient cohorts.

Tim-3, an immune checkpoint inhibitor, plays key roles in maintaining immune homeostasis and is involved in viral evasion. However, the precise role of Tim-3 in viral infection remains to be determined. USP25 is a deubiquitinating enzyme that initiates antiviral immunity by deubiquitinating TRAF3 and triggering the antiviral signaling pathway. Here we found that Tim-3-specific knockout in myeloid cells leads to enhanced antiviral immunity in mice with vesicular stomatitis virus (VSV) encephalitis by increasing the type I interferon response. Mechanistically, Tim-3 inhibits the expression of USP25 via STAT1 and interacts with USP25 but does not regulate its posttranslational modification; as a result, Tim-3 inhibits USP25-mediated deubiquitination of TRAF3, promotes K48-linked ubiquitination and degradation of TRAF3, inhibits the phosphorylation of IRF7, and ultimately downregulates the interferon response. These findings provide new insights into the function of Tim-3 in antiviral immunity and its related clinical significance.

T cell is vital in the adaptive immune system, which relays on T-cell receptor (TCR) to recognize and defend against infection and tumors. T cells are mainly divided into well-known CD4+ and CD8+ T cells, which can recognize short peptide antigens presented by major histocompatibility complex (MHC) class II and MHC class I respectively in humoral and cell-mediated immunity. Due to the Human Leukocyte Antigen (HLA) diversity and restriction with peptides complexation, TCRs are quite diverse and complicated. To better elucidate the TCR in humans, the present study shows the difference between the TCR repertoire in CD4+ and CD8+ T cells from 30 healthy donors. The result showed count, clonality, diversity, frequency, and VDJ usage in CD4+ and CD8+ TCR-β repertoire is different, but CDR3 length is not. The Common Clone Cluster result showed that CD4+ and CD8+ TCR repertoires are connected separately between the bodies, which is odd considering the HLA diversity. More knowledge about TCR makes more opportunities for immunotherapy. The TCR repertoire is still a myth for discovery.

We previously reported that Tim-3, an immune checkpoint inhibitor, inhibits MHC-II expression, but the molecular mechanisms involved and the implications for antiviral immunity remain to be determined. Here, we found that during H1N1 infection, Tim-3 inhibits MHC-II expression in macrophages/microglia in vitro. Tim-3 interacts with MHC-II via its intracellular tail and induces proteasomal dependent degradation of MHC-II. In H1N1 infected macrophages/microglia, Tim-3 promotes the K48-linked ubiquitination of MHC-II via MARCH8, a ubiquitin E3 ligase that can be upregulated by Tim-3. In H1N1 infected mice, specific knockout of Tim-3 in macrophages leads to a decreased viral load, attenuates tissue damage and increases the survival rate. We have thus identified a novel mechanism by which Tim-3 mediates virus immune escape. Manipulating the Tim-3-MHC-II signaling pathway may provide a novel treatment for viral infections.

IntroductionExcessive immune activation induces tissue damage during infection. Compared to external strategies to reconstruct immune homeostasis, host balancing ways remain largely unclear.ObjectivesHere we found a neuroimmune way that prevents infection-induced tissue damage.MethodsBy FACS and histopathology analysis of brain Streptococcus pneumonia meningitis infection model and behavioral testing. Western blot, co-immunoprecipitation, and ubiquitination analyze the Fluoxetine initiate 5-HT7R-STUB1-CCR5 K48-linked ubiquitination degradation.ResultsFluoxetine, a selective serotonin reuptake inhibitor, or the agonist of serotonin receptor 5-HT7R, protects mice from meningitis by inhibiting CCR5-mediated excessive immune response and tissue damage. Mechanistically, the Fluoxetine-5-HT7R axis induces proteasome-dependent degradation of CCR5 via mTOR signaling, and then recruits STUB1, an E3 ubiquitin ligase, to initiate K48-linked polyubiquitination of CCR5 at K138 and K322, promotes its proteasomal degradation. STUB1 deficiency blocks 5-HT7R-mediated CCR5 degradation.ConclusionOur results reveal a neuroimmune pathway that balances anti-infection immunity via happiness neurotransmitter receptor and suggest the 5-HT7R-CCR5 axis as a potential target to promote neuroimmune resilience.

Increasing evidence indicates that immune disorders contribute to the pathogenesis of depression, however the underlying mechanisms and the intervention targets remain to be determined. Here we found that Tim-3, an immune checkpoint inhibitor, is involved in the regulation of depression. The expression of Tim-3 is decreased in a mouse depression model induced by chronic restraint stress, specific deletion of Tim-3 in myeloid cells exacerbated depression as marked by increased cognitive decline. Mechanistically, Tim-3 knock out aggravates neuroimmune inflammation by activating NF-κB and MAPK pathways. Our results reveal that Tim-3 may act as a potential target to promote neuroimmune resilience and thus preventing depression.

Background Calcitonin gene-related peptide (CGRP), an immunomodulatory neuropeptide, is important for regulating pain transmission, vasodilation, and the inflammatory response. However, the molecular mechanisms of the CGRP-mediated immune response remain unknown. Methods The effects of CGRP on bacterial meningitis (BM) and its underlying mechanisms were investigated in BM mice in vivo and macrophages in vitro. Results Peripheral injection of CGRP attenuated cytokine storms and protected mice from fatal pneumococcal meningitis, marked by increased bacterial clearance, improved neuroethology, and reduced mortality. When the underlying mechanisms were investigated, we found that CGRP induces proteasome-dependent degradation of major histocompatibility complex class II (MHC-II) in macrophages and then inhibits CD4+ T-cell activation. MARCH1 was identified as an E3 ligase that can be induced by CGRP engagement and promote K48-linked ubiquitination and degradation of MHC-II in macrophages. These results provide new insights into neuropeptide CGRP-mediated immune regulation mechanisms. Conclusions We conclude that targeting the nervous system and manipulating neuroimmune communication is a promising strategy for treating intracranial infections like BM.

BACKGROUND:A growing number of studies have found that antidepressants have anti-inflammatory effects while protecting nerves. Hypidone hydrochloride (YL-0919) is a novel highly selective 5-HT reuptake blocker. Our previous studies have demonstrated that YL-0919 exerts notable antidepressant- and anxiolytic-like as well as procognitive effects. However, whether YL-0919 can be used to treat inflammatory and infectious diseases remain unknown. In this study, we aimed to verify the anti-inflammatory effect of YL-0919 on bacterial meningitis and further explore the potential molecular mechanisms.METHODS:We performed the experiments on pneumococcal meningitis mice in vivo and S. pneumoniae infected macrophages/microglia in vitro, with or without YL-0919 treatment. Cognitive function was evaluated by open-field task, Morris water maze test, and novel object recognition test. Histopathological staining and immunofluorescence staining were used to detect the pathological damage of meningitis and NLRP3 inflammasome activation in microglia/macrophages. The expression of the STAT1/NLRP3/GSDMD signal pathway was measured by western blots. Proinflammatory cytokines associated with pyroptosis were detected by ELISA.RESULTS:YL-0919 protected mice from fatal pneumococcal meningitis, characterized by attenuated cytokine storms, decreased bacterial loads, improved neuroethology, and reduced mortality. NLRP3 plays a key role in the regulation of inflammation. When the underlying mechanisms were investigated, we found that YL-0919 inhibited the activation of NLRP3 via STAT1, and thus inhibited macrophages/microglia pyroptosis, resulting in downregulation of proinflammatory cytokines. In addition, Sigma1R was identified as a pivotal receptor that can be engaged by YL-0919 to inhibit NLRP3 activation and pyroptosis pathway in microglia/macrophages.CONCLUSIONS:These results provide new insights into the mechanisms of inflammation regulation mediated by the antidepressant YL-0919. Moreover, targeting the STAT1/NLRP3 pyroptosis pathway is a promising strategy for the treatment of infectious diseases like bacterial meningitis.

Chemotherapy-induced neuropathic pain (CIPN) is a common side effect of antitumor chemotherapeutic agents. It describes a pathological state of pain related to the cumulative dosage of the drug, significantly limiting the efficacy of antitumor treatment. Sofas strategies alleviating CIPN still lack. Calcitonin gene-related peptide (CGRP) is a neuropeptide involved in many pathologic pains. In this study, we explored the effects of CGRP blocking on CIPN and potential mechanisms. Total dose of 20.7 mg/kg cisplatin was used to establish a CIPN mouse model. Mechanical and thermal hypersensitivity was measured using von Frey hairs and tail flick test. Western blot and immunofluorescence were utilized to evaluate the levels of CGRP and activated astrocytes in mouse spinal cord, respectively. In addition, real-time quantitative PCR (RT-qPCR) was used to detect the level of inflammatory cytokines such as IL-6, IL-1β, and NLRP3 in vitro and in vivo. There are markedly increased CGRP expression and astrocyte activation in the spinal cord of mice following cisplatin treatment. Pretreatment with a monoclonal antibody targeting CGRP (ZR8 mAb) effectively reduced cisplatin-induced mechanical hypersensitivity and thermal nociceptive sensitization and attenuated neuroinflammation as marked by downregulated expression of IL-6, IL-1β, and NLRP3 in the mice spinal cord and spleen. Lastly, ZR8 mAb does not interfere with the antitumor effects of cisplatin in tumor-bearing mice. Our findings indicate that neutralizing CGRP with monoclonal antibody could effectively alleviate CIPN by attenuating neuroinflammation. CGRP is a promising therapeutic target for CIPN.

Little is known about the distribution of etiology in obstructive sleep apnea (OSA) combined with chronic breathlessness. A significant portion of patients in this group have so-called “overlap syndrome (OVS)”, characterized by chronic obstructive pulmonary disease (COPD). OVS has more complications and a poorer prognosis compared to patients with either OSA or COPD alone, which makes it important to identify OVS early in OSA. The current study was a retrospective cross-sectional analysis of consecutive adult patients who were diagnosed with OSA (n = 1062), of whom 275 were hospitalized due to chronic breathlessness. Respiratory and cardiac diseases accounted for the vast majority of causes, followed by gastrointestinal and renal disorders. The final study population comprised 115 patients with OSA alone (n = 64) and OVS (n = 51), who had chronic breathlessness as the primary complaint, not secondary as one of many other complaints. Lymphocytes, CD4 counts, neutrophil-to-lymphocyte ratio (NLR), and PLR were differently expressed between the OSA-alone group and OVS group. The NLR, lymphocytes, and CD4 counts had a moderate diagnostic value for OVS in OSA patients, with AUCs of 0.708 (95% CI, 0.614–0.802), 0.719 (95% CI, 0.624–0.813), and 0.744 (95% CI, 0.653–0.834), respectively. The NLR had the highest AUC for predicting a 6-month re-admission of OVS, with a cut-off of 3.567 and a moderate prognostic value. The sensitivity and specificity were 0.8 and 0.732, respectively. In the animal model, the spleen hematoxylin- and eosin-stained, electron microscopy images showed germinal-center damage, chromatin activation, and mitochondrial swelling under the overlapping effect of intermittent hypoxia and cigarette smoke exposure. OSA with chronic breathlessness cannot be overstated. A significant proportion of patients with COPD in this group had poor lung function at initial diagnosis. The NLR is a useful biomarker to differentiate OVS among OSA patients combined with chronic breathlessness.

BACKGROUND Calcitonin gene-related peptide (CGRP), an immunomodulatory neuropeptide, is important for regulating pain transmission, vasodilation, and the inflammatory response. However, the molecular mechanisms of the CGRP-mediated immune response remain unknown. METHODS The effects of CGRP on bacterial meningitis (BM) and the underlying mechanisms were investigated in BM mice in vivo and macrophages in vitro. RESULTS Peripheral injection of CGRP-attenuated cytokine storms and protected mice from fatal pneumococcal meningitis, marked by increased bacterial clearance, improved neuroethology, and reduced mortality. When the underlying mechanisms were investigated, we found that CGRP induces proteasome-dependent degradation of MHC-II in macrophages and then inhibits CD4+ T cell activation. MARCH1 was identified as an E3 ligase that can be induced by CGRP engagement and promote K48-linked ubiquitination and degradation of MHC-II in macrophages. These results provide new insights into neuropeptide CGRP-mediated immune regulation mechanisms. CONCLUSIONS Therefore, we conclude that targeting the nervous system and manipulating neuroimmune communication is a promising strategy for treating intracranial infections like bacterial meningitis.

The mechanisms by which retinoic acid-inducible gene I (RIG-I), a critical RNA virus sensor, is regulated in many biological and pathological processes remain to be determined. Here, we demonstrate that T cell immunoglobulin and mucin protein-3 (Tim-3), an immune checkpoint inhibitor, mediates infection tolerance by suppressing RIG-I-type I interferon pathway. Overexpression or blockade of Tim-3 affects type I interferon expression, virus replication, and tissue damage in mice following H1N1 infection. Tim-3 signaling decreases RIG-I transcription via STAT1 in macrophages and promotes the proteasomal dependent degradation of RIG-I by enhancing K-48-linked ubiquitination via the E3 ligase RNF-122. Silencing RIG-I reversed Tim-3 blockage-mediated upregulation of type I interferon in macrophages. We thus identified a new mechanism through which Tim-3 mediates the immune evasion of H1N1, which may have clinical implications for the treatment of viral diseases.