Stroke, in association with its complications, is one of the leading causes of mortality and morbidity worldwide. Cerebral ischemia triggers an inflammatory response in the brain that is controlled by the activation of resident microglia as well as the infiltration of peripheral myeloid and lymphoid cells into the brain parenchyma. This inflammation has been shown to have both beneficial and detrimental effects on stroke outcome. The focus of this review lies on the functions of myeloid cells and their interaction with infiltrating lymphocytes in different phases of stroke. A detailed and time‐specific understanding of the contribution of different immune cell subsets during the course of cerebral ischemia is crucial to specifically promote beneficial and inhibit detrimental effects of inflammation on stroke outcome.

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Alzheimer's disease and small vessel ischemic disease frequently co-exist in the aging brain. However, pathogenic links between these 2 disorders are yet to be identified. Therefore we used Taqman genotyping, exome and RnA sequencing to investigate Alzheimer's disease known pathogenic variants and pathways: APOE ε4 allele, APP-Aβ metabolism and late-onset Alzheimer's disease main genomewide association loci (APOE, BIN1, CD33, MS4A6A, CD2AP, PICALM, CLU, CR1, EPHA1, ABCA7) in 96 early-onset small vessel ischemic disease Caucasian patients and 368 elderly neuropathologically proven controls (HeX database) and in a mouse model of cerebral hypoperfusion. only a minority of patients (29%) carried APOE ε4 allele. We did not detect any pathogenic mutation in APP, PSEN1 and PSEN2 and report a burden of truncating mutations in App-Aß degradation genes. the single-variant association test identified 3 common variants with a likely protective effect on small vessel ischemic disease (0.54>oR > 0.32, adj. p-value <0.05) (EPHA1 p.M900V and p.V160A and CD33 p.A14V). Moreover, 5/17 APP-Aß catabolism genes were significantly upregulated (LogFC > 1, adj. p-val<0.05) together with Apoe, Ms4a cluster and Cd33 during brain hypoperfusion and their overexpression correlated with the ischemic lesion size. finally, the detection of Aβ oligomers in the hypoperfused hippocampus supported the link between brain ischemia and Alzheimer's disease pathology.Late-onset sporadic Alzheimer's disease (LOAD) and small vessel ischemic disease (SVID) frequently influence each other and co-exist in the aging brain depicting a clinical, neuroradiological and neuropathological spectrum defined as 'mixed dementia' . Although mixed dementia represents the second common form of dementia in the elderly, as over 45% of LOAD patients neuropathologically diagnosed displayed significant cerebrovascular pathology 1 , the nature and the pathogenic ground at the basis of AD-SVID interaction is poorly understood 2 . APOE ε4 allele is the strongest risk factor for sporadic LOAD 3-5 , however its role in SVID has not been extensively investigated. Common hallmark in small vessel disease is cerebral amyloid angiopathy (CAA), which is caused by excessive deposition of Aβ 40 and 42 on the walls of small vessels 6,7 , responsible both for its ischemic and hemorragic manifestations (SVID and intracerebral hemorrhage [ICH]) 8 . Both rare familial and common sporadic small vessel disease cases pointed to the potential role of APP-Aß dysmetabolism as key pathogenic mechanism underlying CAA small vessel disease subtype. First, autosomal dominant fully penetrant mutations in the secretase domain of APP, APP duplication, CST3 and TTR rare mutations cause familial CAA 9-11 . Second, common variants in IDE and LRP1 have been associated with increased risk of diabetes type 2 and migraine, respectively, that frequently are co-morbidities in SVID patients 12,13 . Third, perivascular and parenchymal Aß deposits have been reported in genetically diagnosed CADASIL patients and vascular ...

Stroke is one of the leading causes of mortality and morbidity worldwide. Upon cerebral ischemia, an inflammatory reaction takes place in the brain. Infiltration of different immune cell subsets as well as activation of resident microglia cells have been shown to have both beneficial and detrimental effects on stroke outcome. For a long time, research in the field of adaptive immunity after stroke has mostly focused on T lymphocytes and only recently, several publications shed light on the importance of B lymphocytes in the acute and chronic phases of ischemic stroke. In this review, we will focus on the role of B cells in the ischemic brain and describe possible antibody-dependent and antibody-independent mechanisms in the development of post-stroke cognitive deficits.

Stroke is the second leading cause of death and disability worldwide. Current treatments, such as pharmacological thrombolysis or mechanical thrombectomy, reopen occluded arteries but do not protect against ischemia‐induced damage that occurs before reperfusion or neuronal damage induced by ischemia/reperfusion. It has been shown that disrupting the conversion of glyoxal to glycolic acid (GA) results in a decreased tolerance to anhydrobiosis in Caenorhabditis elegans dauer larva and that GA itself can rescue this phenotype. During the process of desiccation/rehydration, a metabolic stop/start similar to the one observed during ischemia/reperfusion occurs. In this study, the protective effect of GA is tested in different ischemia models, i.e., in commonly used stroke models in mice and swine. The results show that GA, given during reperfusion, strongly protects against ischemic damage and improves functional outcome. Evidence that GA exerts its effect by counteracting the glutamate‐dependent increase in intracellular calcium during excitotoxicity is provided. These results suggest that GA treatment has the potential to reduce mortality and disability in stroke patients.

Pneumonia is the most frequent severe medical complication after stroke. An overactivation of the cholinergic signaling after stroke contributes to immunosuppression and the development of spontaneous pneumonia caused by Gram-negative pathogens. The α7 nicotinic acetylcholine receptor (α7nAChR) has already been identified as an important mediator of the anti-inflammatory pathway after stroke. However, whether the α2, α5 and α9/10 nAChR expressed in the lung also play a role in suppression of pulmonary innate immunity after stroke is unknown. In the present study, we investigate the impact of various nAChRs on aspiration-induced pneumonia after stroke. Therefore, α2, α5, α7 and α9/10 nAChR knockout (KO) mice and wild type (WT) littermates were infected with Streptococcus pneumoniae (S. pneumoniae) three days after middle cerebral artery occlusion (MCAo). One day after infection pathogen clearance, cellularity in lung and spleen, cytokine secretion in bronchoalveolar lavage (BAL) and alveolar-capillary barrier were investigated. Here, we found that deficiency of various nAChRs does not contribute to an enhanced clearance of a Gram-positive pathogen causing post-stroke pneumonia in mice. In conclusion, these findings suggest that a single nAChR is not sufficient to mediate the impaired pulmonary defense against S. pneumoniae after experimental stroke.

Stroke-induced immunosuppression contributes to the development of stroke-associated pneumonia (SAP). Experiments in mice demonstrated that apoptosis of IFN-γ producing cells and reduced IFN-γ secretion resulted in impaired immune responses and the development of pneumonia after middle cerebral artery occlusion (MCAo). In the present study, we investigated the efficacy of intratracheal IFN-γ treatment to prevent SAP and demonstrated that modest benefits on pulmonary cytokine response in IFN-γ treated stroke mice did not prevent spontaneously developing infections and even slightly reduced bacterial clearance of aspirated pneumococci. Our results suggest that pulmonary IFN-γ treatment is not an effective preventive measure for SAP.

Recently, several genome-wide association studies identified PHACTR1 as key locus for five diverse vascular disorders: coronary artery disease, migraine, fibromuscular dysplasia, cervical artery dissection and hypertension. Although these represent significant risk factors or comorbidities for ischemic stroke, PHACTR1 role in brain small vessel ischemic disease and ischemic stroke most important survival mechanism, such as the recruitment of brain collateral arteries like posterior communicating arteries (PcomAs), remains unknown. Therefore, we applied exome and genome sequencing in a multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic brain small vessel ischemic disease and CADASIL-like Caucasian patients from US, Portugal, Finland, Serbia and Turkey and in 2 C57BL/6J stroke mouse models (bilateral common carotid artery stenosis [BCCAS] and middle cerebral artery occlusion [MCAO]), characterized by different degrees of PcomAs patency. We report 3 very rare coding variants in the small vessel ischemic disease-CADASIL-like cohort (p.Glu198Gln, p.Arg204Gly, p.Val251Leu) and a stop-gain mutation (p.Gln273*) in one MCAO mouse. These coding variants do not cluster in PHACTR1 known pathogenic domains and are not likely to play a critical role in small vessel ischemic disease or brain collateral circulation. We also exclude the possibility that copy number variants (CNVs) or a variant enrichment in Phactr1 may be associated with PcomA recruitment in BCCAS mice or linked to diverse vascular traits (cerebral blood flow pre-surgery, PcomA size, leptomeningeal microcollateral length and junction density during brain hypoperfusion) in C57BL/6J mice, respectively. Genetic variability in PHACTR1 is not likely to be a common susceptibility factor influencing small vessel ischemic disease in patients and PcomA recruitment in C57BL/6J mice. Nonetheless, rare variants in PHACTR1 RPEL domains may influence the stroke outcome and are worth investigating in a larger cohort of small vessel ischemic disease patients, different ischemic stroke subtypes and with functional studies.