Brain ischemia elicits microglial activation and microglia survival depend on signaling through colony-stimulating factor 1 receptor (CSF1R). Although depletion of microglia has been linked to worse stroke outcomes, it remains unclear to what extent and by what mechanisms activated microglia influence ischemia-induced inflammation and injury in the brain. Using a mouse model of transient focal cerebral ischemia and reperfusion, we demonstrated that depletion of microglia via administration of the dual CSF1R/c-Kit inhibitor PLX3397 exacerbates neurodeficits and brain infarction. Depletion of microglia augmented the production of inflammatory mediators, leukocyte infiltration, and cell death during brain ischemia. Of note, microglial depletion-induced exacerbation of stroke severity did not solely depend on lymphocytes and monocytes. Importantly, depletion of microglia dramatically augmented the production of inflammatory mediators by astrocytes after brain ischemia. In vitro studies reveal that microglia restricted ischemia-induced astrocyte response and provided neuroprotective effects. Our findings suggest that neuroprotective effects of microglia may result, in part, from its inhibitory action on astrocyte response after ischemia.

Astrocytes are believed to bridge interactions between infiltrating lymphocytes and neurons during brain ischemia, but the mechanisms for this action are poorly understood. Here we found that interleukin-15 (IL-15) is dramatically up-regulated in astrocytes of postmortem brain tissues from patients with ischemic stroke and in a mouse model of transient focal brain ischemia. We generated a glial fibrillary acidic protein (GFAP) Infiltrating leukocytes such as lymphocytes are major effectors of postischemic brain inflammation (1-6). The phenotype and function of infiltrating lymphocytes are largely dictated by organspecific intrinsic factors during inflammatory responses (7-9), and such factors in the brain are unique in terms of cellular constituents, blood-brain barrier (10-12), and microenvironment (1-3, 7). As the most abundant cell type in the CNS, astrocytes constitute nearly 50% of the human brain's volume. Astrocytes contribute to the regulation of neural transmission, survival of neurons and other glia cells, and integrity of the blood-brain barrier. In the inflamed CNS, astrocytes engage in significant cross-talk with CNS-infiltrating immune cells by providing a major source of the proinflammatory cytokines and chemokines, thereby activating infiltrating lymphocytes. Evidence has shown that astrocytes can exert potent proinflammatory functions by producing factors including monocyte chemotactic protein-1 (MCP-1/CCL2), interleukin 1 beta (IL-1β), interleukin-6 (IL-6), etc., as their primary mode of action after CNS injury. In addition, astrocytes are considered as important nonprofessional antigen-presenting cells. Depending on the stage of brain pathology, astrocytes also possess antiinflammatory properties such as scar formation and restriction of inflammation by producing transforming growth factor-β (13,14). Recent studies have shown that the inhibition of astrocytes correlates with decreased infarct size (15,16) and that treatments capable of decreasing infarct size are often accompanied by attenuated astrocyte responses. These findings suggest a detrimental role for astrocytes after brain ischemia (15-18). However, still unknown are whether and how astrocytes shape acute CNS immune responses in the context of a postischemic brain and whether this process has any clinical significance.IL-15 belongs to a family of cytokines using the common γ-chain as a component of their receptors (19,20). IL-15 interacts specifically with the high-affinity IL-15 receptor α (IL-15Rα) and binds to IL-2/IL-15Rβ and a common γ-chain expressed by target cells (21-23). In the periphery, monocytes and dendritic cells are the main sources of 25). IL-15 maintains homeostasis and cytotoxic activities of lymphocytes that bear its receptor [i.e., natural killer (NK) and CD8 + T cells] (19,20). Some studies have demonstrated that IL-15 contributes to the immunopathology of several inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease (26,27). Despite recent studies suggesting astrocytes as a major...

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Microglia are the first responders to intracerebral hemorrhage, but their precise role in intracerebral hemorrhage remains to be defined. Microglia are the only type of brain cells expressing the colony-stimulating factor 1 receptor, a key regulator for myeloid lineage cells. Here, we determined the effects of a colony-stimulating factor 1 receptor inhibitor (PLX3397) on microglia and the outcome in the context of experimental mouse intracerebral hemorrhage. We show that PLX3397 effectively depleted microglia, and the depletion of microglia was sustained after intracerebral hemorrhage. Importantly, colony-stimulating factor 1 receptor inhibition attenuated neurodeficits and brain edema in two experimental models of intracerebral hemorrhage induced by injection of collagenase or autologous blood. The benefit of colony-stimulating factor 1 receptor inhibition was associated with reduced leukocyte infiltration in the brain and improved blood–brain barrier integrity after intracerebral hemorrhage, and each observation was independent of lesion size or hematoma volume. These results demonstrate that suppression of colony-stimulating factor 1 receptor signaling ablates microglia and confers protection after intracerebral hemorrhage.

Infections occur commonly after stroke and are strongly associated with an unfavourable functional outcome of these patients. Approaches for effective management of poststroke infection remain scarce, presenting an urgent need for preventive anti-infection strategies for patients who have suffered a stroke. Emerging evidence indicates that stroke impairs systemic immune responses and increases the susceptibility to infections, suggesting that the modification of impaired immune defence could be beneficial. In this review, we summarised previous attempts to prevent poststroke infections using prophylactic antibiotics and the current understanding of stroke-induced immunosuppression. Further elucidation of the immune mechanisms of stroke will pave the way to tailored design of new treatment to combat poststroke infection via modifying the immune system.

The activation of microglia and the various substances they produce have been linked to the pathologic development of Parkinson’s disease (PD), but the precise role of microglia in PD remains to be defined. The survival of microglia depends on colony-stimulating factor 1 receptor (CSF1R) signaling, and CSF1R inhibition results in rapid elimination of microglia in the central nervous system. Using a mouse PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment, we showed that the depletion of microglia via the CSF1R inhibitor PLX3397 exacerbated the impairment of locomotor activities and the loss of dopaminergic neurons. Further, depletion of microglia augmented the production of inflammatory mediators and infiltration of leukocytes in the brain after MPTP exposure. Microglia depletion–induced aggravation of MPTP neurotoxicity was also seen in lymphocyte-deficient mice. In addition, the depletion of microglia did not affect the production of brain-derived neurotrophic factor, but it dramatically augmented the production of inflammatory mediators by astrocytes after MPTP treatment. Our findings suggest microglia play a protective role against MPTP-induced neuroinflammation and dopaminergic neurotoxicity.—Yang, X., Ren, H., Wood, K., Li, M., Qiu, S., Shi, F.-D., Ma, C., Liu, Q. Depletion of microglia augments the dopaminergic neurotoxicity of MPTP.

Myasthenia gravis (MG) is a chronic humoral immunity-mediated autoimmune disorder of the neuromuscular junction characterized by muscle weakness. Follicular helper T (Tfh) cells may be the key Th cell subset that promotes MG development, as their major function is helping B cell activation and Ab production. Aberrance of thymus-derived Tfh cells might be implicated in autoimmune diseases including MG; just how circulating Tfh cells, especially those from patients with a normal thymus, contribute to MG pathogenesis remains to be uncovered. In this article, we characterize a population of circulating CD4(+)CXCR5(+)PD-1(+) Tfh cells in ocular and generalized MG patients without thymic abnormalities and demonstrate that the circulating Tfh cells are significantly enriched in generalized MG patients but not in ocular MG patients compared with healthy subjects, whereas a proportion of follicular regulatory T cells decreased in MG patients. In addition, the frequency of plasma cells and B cells was higher and the serum levels of IL-6/IL-21 were also elevated in these MG patients. The activated Tfh1 and Tfh17 in Tfh cells are the major source for IL-21 production in MG patients. A strong correlation between Tfh cells and the plasma cell frequency and anti-acetylcholine receptor Ab titers was evident in generalized MG patients. In particular, we found that Tfh cells derived from MG patients promoted B cells to produce Abs in an IL-21 signaling-dependent manner. Collectively, our results suggest that circulating Tfh cells may act on autoreactive B cells and thus contribute to the development of MG in patients without thymic abnormalities.

Intracerebral hemorrhage (ICH) is a devastating disease, which accounts for ≈10% to 15% of strokes with high mortality and morbidity.1,2 Effective treatments for ICH remain sparse.1 Accumulating evidence has demonstrated that brain inflammation provoked by microglia and infiltrating lymphocytes exacerbates ICH-induced brain injury.3 After ICH, brain-intrinsic microglia are the first immune responder and followed by inflammatory infiltrates such as neutrophils, monocytes, macrophages, and subsets of lymphocytes. 4,5 Activation of these cellular components together with factors they produce and cell death products, further contribute to brain inflammation, which results in the development of perihematomal edema.3-7 Perihematomal edema can aggravate the mass effect and secondary brain injury through subsequent oligemia and inflammatory insults.1,8 Edema, as a surrogate marker for inflammation in ICH, 1,9,10 and the persistence of perihematomal edema after ictus makes it amenable for intervention.1 Thus, targeting inflammation could be a viable approach for treating ICH.Sphingosine-1-phosphate (S1P) is a ligand for 5 G-proteincoupled receptors: S1P receptors 1 to 5 (S1PR1-5) are responsible for numerous cell-intrinsic and extrinsic activities. 11,12 Fingolimod (FTY720, Glenya), an oral therapy for multiple sclerosis (MS), is a S1PR modulator that binds to S1PR1, 3, 4, and 5. The beneficial effects of fingolimod in MS may be mediated by S1PR1 expressed on lymphocytes, vascular endothelia, neurons, and glia.11 Recent preclinical and clinical studies have demonstrated that fingolimod can attenuate neurodeficits and brain edema in ICH. [13][14][15][16][17][18] However, it remains unclear whether immune modulations via S1PR1 are sufficient for fingolimod to provide Background and Purpose-Preclinical studies and a proof-of-concept clinical study have shown that sphingosine-1-phosphate receptor (S1PR) modulator, fingolimod, improves the clinical outcome of intracerebral hemorrhage (ICH). However, the specific subtype of the S1PRs through which immune modulation provides protection in ICH remains unclear. In addition, fingolimod-induced adverse effects could limit its use in patients with stroke because of interactions with other S1PR subtypes, particularly with S1PR3. RP101075 is a selective S1PR1 agonist with superior cardiovascular safety profile. In this study, we investigated the impact of RP101075 treatment in a mouse model of ICH. Methods-ICH was induced by injection of autologous blood in 294 male C57BL/6J and Rag2 −/− mice. ICH mice randomly received vehicle, RP101075, or RP101075 plus S1PR1 antagonist W146 by daily oral gavage for three consecutive days, starting from 30 minutes after surgery. Neurodeficits, brain edema, brain infiltration of immune cells, blood-brain barrier integrity, and cell death were assessed after ICH. Results-RP101075 significantly attenuated neurological deficits and reduced brain edema in ICH mice. W146 blocked the effects of RP101075 on neurodeficits and brain edema. RP101075 reduced th...