Neuroimmunomodulation最新文献

Although it is well known that severe exercise induces temporary immunosuppression, it remains unclear the effect of gut microbiota on this phenomenon. In this study, to investigate the effect of gut microbiota on the lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production immediately after the exhaustive exercise, C3H/HeN male mice were 1) treated with or without antibiotic (AB), 2) transplanted cecal content from a 5% partially hydrolyzed guar-gum (PHGG) diet, which is classified as low viscous in dietary fiber, fed mice, and 3) intake PHGG diet for 6 wk. The mice were stimulated by LPS administration immediately after loaded forced exhaustive exercise. After the exhaustive exercise, plasma TNF-α concentration in AB mice prior to response from LPS was significantly higher than that in control mice (p<0.01). On the other hand, differences in transplanted cecal contents did not affect TNF-α production by exercise prior to LPS administration. Direct intake of PHGG, however, attenuated the increase in plasma TNF-α concentration in response to LPS, compared with both non-fiber and control diet groups (p<0.01). These results suggest that LPS-induced TNF-α production immediately after intense exercise is regulated depending on both the composition of the gut microbiota and the material being fermented.

Introduction: Lipopolysaccharide (LPS) is widely used to study the mechanisms underlying acute inflammation. Interestingly, several studies suggest that LPS also regulates central dopaminergic signaling. Despite these findings in the brain, the effects of LPS on the dopaminergic system in the periphery remain poorly understood. Notably, peripheral immune cells express dopamine receptors (DRs) and can respond to dopamine. Dysregulation of the dopaminergic system in immune cells has been reported in various chronic inflammatory conditions. Additionally, studies suggest that hypoxia may also modulate dopamine synthesis and potentially amplify LPS-induced effects.

Methods: Thus, the aim of this study was to investigate the effects of peripheral LPS administration on the dopaminergic system in male human peripheral blood mononuclear cells by measuring dopamine plasma levels and the expression of tyrosine hydroxylase and DRs. Additionally, we explored whether these effects are modulated by prior hypoxic exposure.

Results: Our results suggest that in vivo LPS modulates the expression of DRs on monocytes and natural killer cells, as reflected by an upregulation after 24 h. In contrast, the effects of LPS on T and B cells were weaker, with a predominantly inhibitory influence on DR expression, supporting the notion of a cell-specific effect of LPS on dopaminergic signaling within the immune system. Additionally, our results indicate that hypoxic pretreatment did not alter LPS-induced changes in the dopaminergic pathway.

Conclusion: Taken together, this study demonstrates for the first time that systemic LPS administration modulates DR expression in male peripheral immune cells. Further, our in vitro findings suggest that it is the LPS-induced immune response, rather than LPS itself, that drives changes in the dopaminergic pathway in specific immune cell subpopulations. However, further research is needed to elucidate the functional relevance of these findings in clinical contexts.

Introduction: Sleep deficiency is known to increase the risk for multiple disease conditions involving immunopathology, in which inflammation is thought to be a mechanism for disease development. Thus, one potential way to mitigate negative health consequences of deficient sleep is to target inflammation. We investigated whether low-dose acetylsalicylic acid (ASA, aspirin) administration prior to and during exposure to an experimental sleep restriction challenge affects cellular immune responses to sleep restriction.

Methods: We studied 46 healthy humans (19F/27M, age range 19-63 years) in a randomized trial with 3 protocols each consisting of a 14-day at-home phase followed by an 11-day (10-night) in-laboratory stay (sleep restriction/ASA, sleep restriction/placebo, control sleep/placebo) with daily ASA (81 mg/day) or placebo intake across the entire study period (at-home and in-laboratory). During in-laboratory stays, sleep opportunity under both sleep restriction conditions was 8 h during 2 pre-challenge nights, 4 h during 5 nights of restricted sleep, and 8 h during 3 nights of recovery sleep. Under the control sleep condition, participants had a sleep opportunity of 8 h/night throughout the protocol. Blood samples were analyzed prior to and following 5 nights of sleep restriction/control sleep, and after 2 nights of recovery sleep. Data were analyzed using generalized linear mixed models.

Results: Experimental sleep restriction increased WBC, lymphocyte, monocyte, eosinophil, basophil, CD4 T cell counts, and the CD4/CD8 T cell ratio compared to control sleep under placebo (p<.01). Low-dose ASA had no effect at pre-challenge for most cell types. However, low-dose ASA attenuated the eosinophil and basophil responses to sleep restriction and reduced elevation of the CD4/CD8 T cell ratio (p<.01). Monocyte counts stayed elevated after 2 nights of recovery sleep in the sleep restriction/ASA condition compared to control sleep, whereas monocyte counts recovered under placebo intake (p<.01).

Conclusion: The present study shows that low-dose ASA can counteract certain cellular immune responses to sleep restriction, in particular elevations in eosinophil and basophil counts as well as the CD4/CD8 T cell ratio, while not affecting most immune cell counts prior to the sleep restriction challenge.

Trial registration: ClinicalTrials.gov NCT03377543.

Background: Aging is associated with enumerative and functional changes of peripheral innate immune cells, notably myeloid cells (e.g., monocytes/macrophages and neutrophils). Peripheral myeloid cells routinely infiltrate the brain, particularly at the brain borders, influencing cognition, mood, and stress responses.

Summary: Here, we review how the dysfunctional crosstalk between circulating myeloid cells and brain cells may contribute to the development of late-life depression and Alzheimer's disease during aging. The aged cerebral microglia (i.e., resident macrophages) exhibit dystrophic morphology and impaired phagocytosis while peripheral myeloid cells expand in number but display functional deficits, including impaired phagocytosis and pro-inflammatory biased response. The peripheral myeloid changes collectively contribute to systemic chronic inflammation and tissue dysfunction. Epigenetic changes and metabolic disruptions, such as altered glucose utilization, exacerbate pro-inflammatory states.

Key messages: The cumulative impact of these alterations undermines neuroprotection and facilitates age-related neuropsychiatric conditions, including neurodegenerative diseases and late-life depression. The identification of pro-aging circulating factors and cells could pave the way for new therapeutic strategies aimed at mitigating cognitive decline and improving mood. Targeting myeloid cell metabolism or inflammatory signaling pathways emerges as a promising strategy to mitigate aging-associated neuropsychiatric syndromes.

Background: Neuroimmunology focuses on the two-way communication between the nervous and immune systems, a crucial relationship that maintains the body's internal balance. Disruptions in this neural-immune axis are associated with several disorders.

Summary: Fatty acids, as bioactive molecules, can modulate both neural and immune functions. Saturated fatty acids (SFAs) and polyunsaturated fatty acids (PUFAs) have opposite effects: SFAs promote inflammation and are associated with neurodegenerative diseases and cognitive impairment, whereas PUFAs exhibit anti-inflammatory and neuroprotective properties. The balance between SFAs and PUFAs is key in regulating neuroimmune interactions.

Key messages: Fatty acid receptors act as essential molecular sensors, connecting lipid signaling to both immune and neural outcomes, and their activation or inhibition influences cytokine production and neuron survival. Due to their role in these pathways, targeting fatty acid interactions to control inflammation and promote neural repair represents a promising strategy for neurological disease therapies. This review examines how fatty acids influence neuroimmune cells and may pave the way for the development of new therapeutic approaches.

Background: Tuberculosis (TB) remains a leading cause of mortality worldwide among infectious agents, and HIV increases the risk of developing into active disease. HIV-TB coinfection impairs immune responses, while chronic inflammation and infection-associated stress activate neuroendocrine pathways that deeply impact immune homeostasis. Adrenal steroids such as cortisol, dehydroepiandrosterone (DHEA) and its metabolites, along with metabolic hormones like leptin and adiponectin, have emerged as critical regulators of immune function, although their role in TB pathogenesis, particularly in co-infected individuals, remains underexplored.

Summary: This review navigates over current evidence on the neuroendocrine-immune crosstalk in HIV-TB coinfection, focusing on adrenal and metabolic hormonal axes. We first summarize how HIV-driven CD4+ T cell depletion, chronic immune activation, and altered granuloma dynamics predispose individuals to TB reactivation. We then examine findings indicating that TB and HIV disrupt hypothalamic-pituitary-adrenal (HPA) axis homeostasis, leading to elevated cortisol levels, reduced DHEA and its metabolites, and an unfavorable cortisol/DHEA ratio, which correlated with poor immune control and disease severity. Preclinical studies highlight immunomodulatory properties of DHEA derivatives, such as 7-oxo-DHEA (7-OD), which restore Th1 responses, limit Treg expansion, and enhance macrophage antimicrobial activity. Metabolic hormones, particularly leptin and adiponectin, further shape host immunity and energy allocation; their dysregulation in coinfection contributes to wasting, impaired granuloma formation, and increased immune reconstitution inflammatory syndrome (IRIS) risk. Despite compelling preclinical findings, clinical studies on hormonal modulation remain scarce, emphasizing the need for translational research that links endocrinology and infectious disease immunology.

Key messages: HIV-TB coinfection creates a neuroendocrine-immune imbalance, with dysregulation of the HPA axis and metabolic hormones contributing to impaired immune control and accelerated disease progression. Adrenal hormones such as DHEA and its metabolite 7-oxo-DHEA show potential as immunomodulatory agents, capable of restoring Th1 responses, limiting Treg expansion, and supporting host-directed therapies. Additionally, leptin and adiponectin emerge as crucial metabolic players that integrate nutritional status and immune activity and may serve as potential biomarkers for TB management. Altogether, integrating endocrine profiling into TB research and advancing the clinical evaluation of hormonal immunomodulators may unlock novel avenues for precision medicine, improving treatment strategies for populations affected by the HIV and TB epidemics.

Background: Pneumonia is an infection that affects the alveolar spaces of the lungs, associated with high global mortality, and remains a significant public health challenge worldwide. In a compromised immune system, the infection can progress, leading to the establishment of pneumonia. During this process, an intense inflammatory response is triggered in the lungs through the activation of resident immune cells, especially alveolar macrophages. This activation promotes the recruitment of neutrophils and the release of pro-inflammatory cytokines, ultimately resulting in the formation of exudative infiltrates within the alveoli. Pneumonia is a leading cause of sepsis, particularly among hospitalized patients and in intensive care units. Sepsis represents one of the most severe complications of pneumonia and is characterized by a dysregulated systemic inflammatory response to lung infection. Another critical challenge to treating clinical infectious conditions, which can lead to life-threatening sepsis, septic shock, and multiorgan dysfunction, is the continuous growth of antimicrobial resistance in bacteria.

Summary: Among the organ dysfunctions associated with sepsis, sepsis-associated encephalopathy (SAE) is the most frequent and constitutes a primary contributor to the neurological alterations observed in critically ill patients. Although SAE is often classified as a fully reversible pathophysiological process, increasing evidence suggests an association between sepsis, structural brain injury, and long-term neurological sequelae. The central nervous system (CNS) is one of the first regions exposed to peripheral inflammation during sepsis, allowing inflammatory mediators and immune cells to infiltrate the brain. This process activates microglia, the resident immune cells of the CNS, exposing neurons to an oxidative stress-rich environment that leads to neuronal dysfunction and apoptosis. A dysregulated pro-inflammatory microglial response plays a significant role in SAE, as microglia-derived cytokines are strongly associated with neuronal damage. Furthermore, activated microglia stimulate astrocytes to adopt a reactive inflammatory phenotype, thereby amplifying neuroinflammation.

Key messages: Recent studies have demonstrated that regulating microglial and astrocytic hyperactivation can attenuate the inflammatory response. Therefore, targeting glial cells during SAE holds significant therapeutic potential, offering a promising avenue for the development of new strategies aimed at reversing the exacerbated CNS inflammatory response, mitigating neuronal damage, and ultimately reducing the long-term neurological sequelae observed in post-septic patients.

Background: Although this seems to be common knowledge among experts, it is important to remind readers that two populations, namely, brain microglia and macrophages, found in different compartments of the central nervous system, play essential roles in innate neuroimmunology.

Summary: Here, some historical and conceptual background will be provided that should allow the reader to place recent findings on these cells in some context and perspective.

Key messages: It will be argued that (1) the brain is not devoid of immune response, but does represent an immune-privileged site, (2) innate neuroimmunology concerns brain border macrophages and parenchymal microglia, (3) even though brain border macrophages have been less extensively studied than parenchymal microglia, it is progressively becoming clear that these populations play different roles in physiological and pathological conditions and (4) while it is tempting to only use the latest technologies to obtain new findings, it is also essential, for the sake of science, to "triangulate" with findings obtained with more classic approaches. To determine whether and when innate neuroimmune responses are protective or pathological will be an important aim for future research.