Acute ischemic stroke is one of the leading causes of mortality and morbidity worldwide. The underlying inflammation process following the ischemic event arises as an important factor of great therapeutic interest. Recent research has showcased the roles of B- and T-lymphocytes in the acute post-stroke period, with various types of lymphocytes affecting differently the clinical outcome of the patient. Herein, we reviewed the literature and discussed the functional role of various subpopulations of lymphocytes in recovery and repair of the ischemic tissue as well as their influence on the final outcome of the patient. Additionally, we searched the literature regarding current knowledge on various drugs possibly affecting neuroinflammation or exhibiting a neuroprotective role in the acute post-stroke period.

BackgroundMénière disease (MD) is a chronic inner ear disorder of unknown etiology. Although an immune-inflammatory link is suspected, the upstream triggers and cellular mechanisms connecting psychosocial stress to inner ear pathology remain poorly defined. This study aimed to investigate the role of stress-related, myeloid cell-derived inflammation in the progression of MD.MethodsThis multi-cohort study involved 384 MD patients (62.5% female); and 138 healthy controls (HCs) (46.4% female). Perceived stress was evaluated in 110 MD patients and 65 HCs. Transcriptional profiles were characterized using RNA sequencing on peripheral whole blood (4 MD, 6 HC) and on sorted CD11b + myeloid cells versus CD11b-non-myeloid cells (8 MD, 6 HC). In a larger cross-sectional cohort (239 MD patients, 35 HCs), the association between serum inflammatory cytokines and audio-vestibular function was examined, with a subset (n = 42) followed up. Finally, in vitro experiments explored the regulatory effects of catecholamines and glucocorticoids on myeloid cells isolated from 23 MD patients and 26 HCs.ResultsMD patients reported significantly higher levels of perceived stress compared to controls. RNA sequencing of peripheral blood revealed a distinct pro-inflammatory transcriptional signature in MD patients. Further analysis identified CD11b + myeloid cells as the primary source of this inflammation, showing significant upregulation of pro-inflammatory genes. Clinically, elevated serum levels of the myeloid-derived cytokine G-CSF were associated with poorer baseline audio-vestibular function, and a follow-up increase in G-CSF levels correlated with functional deterioration. Mechanistically, MD patients exhibited elevated plasma norepinephrine and increased β1-adrenergic receptor mRNA in myeloid cells. In vitro, blockade of the β-adrenergic-cAMP pathway attenuated pro-inflammatory cytokine production in these cells. Although systemic cortisol levels remained unchanged, the glucocorticoid receptor sensitivity of myeloid cells in MD patients was altered.ConclusionOur study elucidates a potential pathophysiological axis in MD, where perceived psychosocial stress is linked to sympathetic nervous system overactivity. This, in turn, primes circulating myeloid cells for a pro-inflammatory response via the β-adrenergic pathway. The resultant systemic inflammation is closely associated with the severity and progression of audio-vestibular dysfunction. These findings suggest that targeting the stress-neuroendocrine-immune interface may offer novel therapeutic strategies for MD.

Women affected by obstructive sleep apnea (OSA) face an increased risk of cognitive impairment and mood disorders, with emerging evidence suggesting that neuroinflammation plays a significant role in the pathophysiology. OSA causes intermittent hypoxia and activates the immune response in the brain. Additionally, menopause is a separate risk factor that can put women with OSA at an even higher risk of cognitive decline. Although neuroinflammation occurs in OSA, the underlying mechanisms of the neuroinflammatory response are not well understood, and it remains unknown whether ovarian hormones modify these mechanisms. To examine the impact of OSA and hormone status on neuroinflammation, we used a 7-day chronic intermittent hypoxia (CIH) and ovariectomy (OVX) to model OSA and hormone status in female rats, respectively. To examine neuroinflammation, we investigated changes in brain microglia and astrocyte morphology and the number of reactive cells. We used a comprehensive three-dimensional reconstruction and analysis of microglia and astrocytes to study the changes in the morphology of these cells. We focused on brain regions associated with cognitive function (CA1 of the dorsal hippocampus, medial prefrontal cortex – mPFC, caudate and putamen – CP). Specifically, immunofluorescence of Iba1 (microglia marker) and GFAP (astrocyte marker) was conducted, along with measuring indicators of glial reactivity (branching, complexity, cell size, and number of reactive cells). Our results found that there were CIH and hormone effects on neuroinflammation in these brain regions. Microglia activation was impacted by an interaction between CIH and hormone status in all regions examined. In contrast, astrocytes showed no reactivity in all regions examined, regardless of CIH or hormone status. These findings suggest that menopause and OSA may impact microglia remodeling in brain areas associated with cognitive function. Microglia-specific neuroinflammation may be part of early mechanisms that lead to the cognitive impairments observed in CIH and hormone loss in females.

Amyloid beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles (NFTs) are the histopathological hallmarks of Alzheimer's disease (AD) and targets for AD therapeutics. Since Aβ and tau pathologies both drive AD pathogenesis and progression, immunotherapies singularly targeting either Aβ or tau may be limited, and simultaneously targeting multiple epitopes of both Aβ and tau may be an efficacious approach. We developed a novel vaccine including three his-tagged tau peptides, tau1-22, mid-region tau171-191 (taupT181), and tau388-407 (taupS396/S404), as well as two his-tagged Aβ fragments (N-terminal Aβ1-14 and N-terminal pyroglutamate AβpE3-14) with the spontaneous nanoliposome antigen particle (SNAP) system, termed SNAP-AD5. Intramuscular vaccination of nine to ten months old of 3xTg-AD mice and age-matched wild-type control animals with SNAP-AD5 or adjuvant only, once every three weeks for a total of 5 immunizations, simultaneously produced IgG titers of antibody against their specific antigens, significantly decreased Aβ and tau pathologies, and effectively improved cognitive function. SNAP-AD5 was well tolerated without any detectable adverse side effects, including inflammatory responses in the peripheral circulation and in the brain, and hemorrhages in the mouse brain. These results support that SNAP-AD5 simultaneously targeting both Aβ and tau is potentially a promising new approach for treating AD. Further optimization and development of the SNAP-AD5 vaccine for treating AD is warranted.