Neuroimmunomodulation最新文献

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.

Introduction: Rheumatoid arthritis (RA) can be comorbid with psychiatric symptoms. Brain abnormalities in RA patients and in arthritis models have been reported. However, it remains unclear when these abnormalities occur and where they are distributed. In this study, we analyzed spatiotemporal changes in gene expression in the brains of mice with collagen-induced arthritis (CIA).

Methods: Mice were divided into three groups: (i) CIA (all mice developed arthritis on day 35): complete Freund's adjuvant (CFA) and type II collagen at initial immunization, and incomplete Freund's adjuvant (IFA) and type II collagen at booster immunization; (ii) C(+/-) (50% mice developed arthritis on day 35): only IFA at booster immunization; and (iii) C(-/-) (no arthritis): only CFA at initial immunization and only IFA at booster immunization. Whole brains were collected at ten stages of arthritis and divided into six sections. Real-time polymerase chain reaction was performed using RNA extracted from the brain, and the expression of proinflammatory cytokines and glial markers was semi-quantified. Arthritis score, body weight, and food and water intakes were recorded and analyzed for correlations with brain gene expression. We also investigated the effect of interleukin-6 (IL-6) injection in the olfactory bulbs (OBs) on the food intake.

Results: After booster immunization, a transient increase in Integrin subunit α-M and IL-1β was observed in multiple areas in CIA. IL-6 is persistently expressed in the OB before the onset of arthritis, which is correlated with body weight loss and decreased food intake. This change in the OB was observed in the C(+/-) but not in the C(-/-) groups. In the C(+/-) group, non-arthritic mice showed the same changes in the OB as the arthritic mice. This elevation in IL-6 levels persisted throughout the chronic phase until day 84. In addition, IL-6 injection into the OB reduced food intake.

Conclusion: Persistent elevation of IL-6 in the OB from the early stage of arthritis may be an important finding that might explain the neuropsychiatric pathophysiology of RA, including appetite loss, which is present in the early stages of the disease and manifests as a variety of symptoms over time.

Introduction: In an attempt to avoid contact with infectious individuals, humans likely respond to generalized rather than specific markers of disease. Humans may thus perceive a noninfectious individual as socially less attractive if they look (e.g., have facial discolouration), move (e.g., have a slower walking pace), or sound (e.g., sneeze) sick. This pilot study tested whether humans are averse to the body odour of noninfectious individuals with a low-grade systemic inflammation.

Methods: We collected the axillary body odour of individuals with severe seasonal allergy (N = 14) and healthy controls (N = 10) during and outside the allergy season and measured serum levels of two inflammatory cytokines (tumour necrosis factor-α and interleukin-5). Independent participants (N = 67) then sampled and rated these odours on intensity and pleasantness.

Results: While individuals with seasonal allergy had nominally more unpleasant and intense body odours during the allergy season, relative to outside the allergy season and to healthy controls, these effects were not significant. When examining immune markers, the change in perceived pleasantness of an individual's body odour (from out-to-inside pollen season) was significantly related to the change in their interleukin-5 levels but not to tumour necrosis factor-α.

Discussion: Our findings tentatively suggest that the human olfactory system could be sensitive to inflammation as present in a noncommunicable condition. Larger replications are required to determine the role of olfaction in the perception of infectious and noninfectious (e.g., chronic diseases) conditions.

The sympathetic nervous system (SNS) is a major regulatory mediator connecting the brain and the immune system that influences accordingly inflammatory processes within the entire body. In the periphery, the SNS exerts its effects mainly via its neurotransmitters norepinephrine (NE) and epinephrine (E), which are released by peripheral nerve endings in lymphatic organs and other tissues. Depending on their concentration, NE and E bind to specific α- and β-adrenergic receptor subtypes and can cause both pro- and anti-inflammatory cellular responses. The co-transmitter neuropeptide Y, adenosine triphosphate, or its metabolite adenosine are also mediators of the SNS. Local pro-inflammatory processes due to injury or pathogens lead to an activation of the SNS, which in turn induces several immunoregulatory mechanisms with either pro- or anti-inflammatory effects depending on neurotransmitter concentration or pathological context. In chronic inflammatory diseases, the activity of the SNS is persistently elevated and can trigger detrimental pathological processes. Recently, the sympathetic contribution to mild chronic inflammatory diseases like osteoarthritis (OA) has attracted growing interest. OA is a whole-joint disease and is characterized by mild chronic inflammation in the joint. In this narrative article, we summarize the underlying mechanisms behind the sympathetic influence on inflammation during OA pathogenesis. In addition, OA comorbidities also accompanied by mild chronic inflammation, such as hypertension, obesity, diabetes, and depression, will be reviewed. Finally, the potential of SNS-based therapeutic options for the treatment of OA will be discussed.