Neuroimmunomodulation最新文献

Introduction: Inflammatory pain is a significant global clinical challenge that involves both unpleasant sensory and emotional experiences. The treatment of pain is imminent, and we are committed to seeking new analgesics for pain relief. Transcrocetin meglumine salt (TCMS), a saffron metabolite derived from the crocin apocarotenoids, has exhibited the ability to cross the blood-brain barrier and exert neuroprotective effects. In this study, we aimed to investigate whether TCMS could ameliorate complete Freund's adjuvant (CFA)-induced inflammatory pain in mice and elucidate its underlying mechanisms.

Methods: Here, we established an inflammatory pain model in mice by injecting CFA into the left hind paw. Three days later, we administered intraperitoneal injections of TCMS (10 mg/kg) or saline to the animals. We examined mechanical allodynia, thermal hypersensitivity, and anxiety behavior. Furthermore, the activation of glial cells and proinflammatory cytokines in the spinal cord were detected.

Results: Our results showed that TCMS significantly reversed the mechanical allodynia and thermal hypersensitivity in the CFA-injected mice. Furthermore, TCMS administration effectively inhibited the activation of microglia and astrocytes in the spinal cord induced by CFA. Additionally, TCMS suppressed the production and release of spinal proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, in CFA-injected mice.

Conclusion: Taken together, our findings demonstrate that TCMS holds promise as an innovative analgesic due to its ability to ameliorate inflammatory reactions.

Introduction: In the present work, the frequency of inherited polymorphisms of the beta 2 adrenergic receptor (β2AR) gene and their association with fatigue in patients with rheumatoid arthritis (RA) was examined.

Methods: An allele-specific polymerase chain reaction was used to determine the common variants of the β2AR at position 16, 27, and 164 in 92 German RA outpatients. Health Assessment Questionnaire (HAQ-DI), Beck Depression Inventory (BDI), Perceived Stress Questionnaire (PSQ-30), Multidimensional Fatigue Inventory (MFI-20) were utilized.

Results: 34.7% of German RA patients were diagnosed with associated fatigue. Fatigued patients were more likely to carry the Ile allele at position 164 (OR 7.33, 95% CI 1.09-59.8, p = 0.049). Comparing these risk factors' contribution to different fatigue dimensions revealed that Ile164 carriers only had significantly higher MFI-20 mean values for general fatigue (p = 0.014) while the clinical difference among other MFI subscales was the largest for mental fatigue (carrier: 8.23, SD: 4.22, noncarrier: 5.67, SD: 1.56, p = 0.089, Cohen's d = 0.629). Disease activity, perceived stress, and depression were also associated with fatigue with higher mean values for DAS28CRP (p = 0.038), PSQ (p < 0.001), and BDI-II (p < 0.001) in fatigued patients. Physical fatigue was correlated with disease activity (p = 0.009) and depression (p = 0.001) while mental fatigue showed associations with depression (p = 0.001) and perceived stress (p = 0.028).

Conclusion: The discovery study indicates that the Ile164 polymorphism might in contrast to other β2AR polymorphisms affect fatigue levels in RA patients. This association was observed especially with mental fatigue. Further replication studies are warranted to determine further role of β2AR polymorphisms in RA patients.

The assumption of the pineal hormone melatonin as a therapeutic use for COVID-19-affected people seems promising. Its intake has shown significant improvement in the patients' conditions. Higher melatonin titers in children may provide a protective shield against this disease. The hormone melatonin works as an anti-inflammatory, antioxidant, immunomodulator, and strategically slows down the cytokine release which is observed in the COVID-19 disease, thereby improving the overall health of afflicted patients. The medical community is expected shortly to use remedial attributes like anti-inflammatory, antioxidant, antivirals, etc., of melatonin in the successful prevention and cure of COVID-19 morbidity. Thus, the administration of melatonin seems auspicious in the cure and prevention of this COVID-19 fatality. Moreover, melatonin does not seem to reduce the efficiency of approved vaccines against the SARS-CoV-2 virus. Melatonin increases the production of inflammatory cytokines and Th1 and enhances both humoral and cell-mediated responses. Through the enhanced humoral immunity, melatonin exhibits antiviral activities by suppressing multiple inflammatory products such as IL-6, IL1β, and tumor necrosis factor α, which are immediately released during lung injury of severe COVID-19. Hence, the novel use of melatonin along with other antivirals as an early treatment option against COVID-19 infection is suggested. Here, we have chalked out the invasion mechanisms and appropriate implications of the latest findings concerned with melatonin against the virus SARS-CoV-2. Nevertheless, within the setting of a clinical intervention, the promising compounds must go through a series of studies before their recommendation. In the clinical field, this is done in a time-ordered sequence, in line with the phase label affixed to proper protocol of trials: phase I-phase II and the final phase III. Nevertheless, while medical recommendations can only be made on the basis of reassuring evidence, there are still three issues worth considering before implementation: representativeness, validity, and lastly generalizability.

Introduction: This study aimed to investigate the possible role of galectin-3 in epilepsy and further explore its underlying mechanisms.

Methods: Sprague-Dawley rats were intraperitoneally injected with 30 mg/kg pilocarpine to induce an animal model of epilepsy. To inhibit galectin-3, the epilepsy model of rats was intraperitoneally injected with TD139. The severity of the seizure was graded according to the Racine score. The pathological changes in hippocampal CA1 regions were observed by hematoxylin and eosin and Nissl staining. Enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and Western blot were used to detect the levels of cytokines and pyroptosis-related factors. The in vitro effects of galectin-3 were confirmed on BV2 cells and rat primary microglia by transfection with lentivirus vectors carrying Lgals3 shRNA or by treatment with TD139.

Results: A higher expression of galectin-3 was observed in the hippocampal CA1 regions of epilepsy rats than in sham rats. Inhibition of galectin-3 by administration of TD139 improved the severity of the seizure, hippocampal damage, and neuron loss. TD139 administration suppressed the expression of NLRP3, ASC, c-caspase-1, and GSDMD-N, and reduced the levels of cytokines. In kainic acid-treated microglia, Lgals3 shRNA or TD139 significantly inhibited Iba1 expression and limited NLRP3/pyroptosis-triggered inflammation.

Conclusion: Galectin-3 activates the NLRP3/pyroptosis signaling pathway to promote microglial activation and neuroinflammation during epilepsy disease progression.

In this review, we will try to convince the readers that the immune system is controlled by an endogenous neural reflex, termed inflammatory reflex, that inhibits the acute immune response during the course of a systemic immune challenge. We will analyse here the contribution of different sympathetic nerves as possible efferent arms of the inflammatory reflex. We will discuss the evidence that demonstrates that neither the splenic sympathetic nerves nor the hepatic sympathetic nerves are necessary for the endogenous neural reflex inhibition of inflammation. We will discuss the contribution of the adrenal glands to the reflex control of inflammation, noting that the neurally mediated release of catecholamines in the systemic circulation is responsible for the enhancement of the anti-inflammatory cytokine interleukin 10 (IL-10) but not of the inhibition of the pro-inflammatory cytokine tumour necrosis factor α (TNF). We will conclude by reviewing the evidence that demonstrates that the splanchnic anti-inflammatory pathway, composed by preganglionic and postganglionic sympathetic splanchnic fibres with different target organs, including the spleen and the adrenal glands, is the efferent arm of the inflammatory reflex. During the course of a systemic immune challenge, the splanchnic anti-inflammatory pathway is endogenously activated to inhibit the TNF and enhance the IL-10 response, independently, presumably acting on separate populations of leukocytes.

Introduction: Excessive stress is increasingly recognized as an important trigger of many diseases prevalent in modern societies, and monitoring such stress-related effects could aid prevention. The measurement of salivary markers of inflammation is emerging as a promising tool to non-invasively quantify stress' effects on immune processes in everyday life and thereby detect early aberrations before the manifestation of serious health problems. However, more laboratory-controlled research is needed in order to establish the timescale and determinants of salivary cytokine responses to acute stress.

Methods: We repeatedly exposed participants to Cold Pressor Stress Test (CPT) or a control procedure and measured a wide array of salivary cytokines as well as subjective, cardiovascular, and cortisol stress reactions. CPT exposure was repeated every 15 min, 3 times in total, with a duration of 3 min each. Saliva was sampled immediately after the first two exposures as well as in 15-min intervals until 60 min after the onset of the first intervention.

Results: We found that many cytokines were detectable in saliva. Specific stress effects were limited to IL-8 and IL-6, however, which decreased immediately or 15 min after stress onset, respectively. Moreover, IL-8 was negatively correlated to cortisol output in the stress but not in the control group. Significant increases were also observed in salivary TNFα and IFNγ; however, these effects were similar under both stress and control conditions.

Discussion: Our results show that particular salivary cytokines may be sensitive to immediate effects of acute CPT-induced stress and also highlight the importance of employing control procedures to discern stress effects from unrelated variations in salivary cytokines.

Interleukin (IL)-33 was initially recognized as a constituent of the IL-1 cytokine family in 2005. It exerts pleiotropic effects by regulating immune responses via its binding to the receptor ST2 (IL-33R). The IL-33/ST2 pathway has been linked to several inflammatory disorders. In human and rodents, the broad expression of IL-33 in spinal cord tissues and brain indicates its central nervous system-specific functions. Growing evidence supports the protective effects of the IL-33/ST2 pathway in ischemic stroke, along with a better understanding of the underlying mechanisms. IL-33 plays a crucial role in the regulation of the release of inflammatory molecules from glial cells in response to neuropathological lesions. Moreover, IL-33/ST2-mediated neuroprotection following cerebral ischemia may be linked to T-cell function, specifically regulatory T cells. Soluble ST2 (sST2) acts as a decoy receptor in the IL-33/ST2 axis, blocking IL-33 signaling through the membrane ST2 receptor. sST2 has also been identified as a potential inflammatory biomarker of ischemic stroke. Targeting sST2 specifically to eliminate its inhibition of the protective IL-33/ST2 pathway in ischemic brain tissues is a promising approach for the treatment of ischemic stroke.

The immune system and the central nervous system exchange information continuously. This communication is a prerequisite for adaptive responses to physiological and psychological stressors. While the implicate relationship between inflammation and pain is increasingly recognized in clinical cohorts, the underlying mechanisms and the possibilities for pharmacological and psychological approaches aimed at neuro-immune communication in pain are not fully understood yet. This calls for preclinical models which build a bridge from clinical research to laboratory research. Experimental models of systemic inflammation (experimental endotoxemia) in humans have been increasingly recognized as an approach to study the direct and causal effects of inflammation on pain perception. This narrative review provides an overview of what experimental endotoxemia studies on pain have been able to clarify so far. We report that experimental endotoxemia results in a reproducible increase in pain sensitivity, particularly for pressure and visceral pain (deep pain), which is reflected in responses of brain areas involved in pain processing. Increased levels of blood inflammatory cytokines are required for this effect, but cytokine levels do not always predict pain intensity. We address sex-dependent differences in immunological responses to endotoxin and discuss why these differences do not necessarily translate to differences in behavioral measures. We summarize psychological and cognitive factors that may moderate pain sensitization driven by immune activation. Together, studying the immune-driven changes in pain during endotoxemia offers a deeper mechanistic understanding of the role of inflammation in chronic pain. Experimental endotoxemia models can specifically help to tease out inflammatory mechanisms underlying individual differences, vulnerabilities, and comorbid psychological problems in pain syndromes. The model offers the opportunity to test the efficacy of interventions, increasing their translational applicability for personalized medical approaches.

Introduction: Multiple sclerosis (MS) is a neurodegenerative autoimmune disease that worsens with age. Here, we examined the influence of age on passive experimental autoimmune encephalomyelitis (P-EAE), a model to study MS, using young and mature adult 2D2 transgenic donor mice to induce pathology in WT C57BL6/J mice.

Methods: Lymphocytes from young adult (i.e., 10-week-old) or mature adult (i.e., 6-month-old) transgenic donor mice were characterized by flow cytometry prior to injection of cultured leukocytes into adult female WT recipient mice, with a special focus on transgenic T cell phenotypes.

Results: Our findings show age-dependent changes in memory T cell phenotypes correlated with more severe clinical and histological disease when donor cells originated from young as compared to mature adult mice.

Conclusion: Not only do these results demonstrate that the age of the 2D2 transgenic donor mice is critical in establishing P-EAE, but the differential effects might also identify age-dependent factors that contribute to EAE and perhaps MS.

Introduction: Dendritic cells (DCs) play critical roles in the pathogenesis of myasthenia gravis (MG), and a series of DC-based experimental strategies for MG have recently been developed. However, the definite roles of different DC subsets in the mechanism of MG have scarcely been covered by previous studies. The present study aimed to investigate the levels of three main DC subsets, plasmacytoid DCs (pDCs) (CD303 positive) and two distinct subsets of conventional DCs (cDCs), namely CD1c+ cDCs and CD141+ cDCs, in MG patients and analyze related clinical features.

Methods: From January 2016 to December 2020, 160 newly diagnosed MG patients and matched healthy controls (n = 160) were included in the study, and their clinical data were collected. The blood samples from MG patients before treatment and controls were collected for flow cytometry analysis. A total of 14 MG thymoma, 24 control thymoma, and 3 thymic cysts were used to immunostain the DC subsets.

Results: The flow cytometry analysis showed a significantly higher frequency of circulating pDCs, CD1c+ cDCs, and CD141+ cDCs in MG patients than in healthy controls (p < 0.001 for all). Patients with early-onset MG (<50 years old) had a lower frequency of circulating pDCs but a higher frequency of circulating CD1c+ cDCs than those with late-onset MG (≥50 years old) (p = 0.014 and p = 0.025, respectively). The frequency of circulating pDCs was positively associated with the clinical severity of late-onset MG patients (r = 0.613, p < 0.001). 64.3% (9/14) of MG thymoma is of type B2 under the World Health Organization classification, which is higher than that in control thymoma (33.3%, 8/24) (p = 0.019). For type B2 thymoma, there were significantly more pDCs but fewer CD1c+ cDCs in MG thymoma than in the controls.

Conclusion: The distribution of aberrant pDCs, CD1c+ cDCs, and CD141+ cDCs in MG patients displayed age- and thymoma-related differences, which may contribute to the impaired immune tolerance and lead to the onset of MG.