have shown that CD5+CD1dhi B10 cells are enriched in the ipsilateral versus contralateral hemisphere of mice at 48 h post-stroke, as well as circulating regulatory B-cells (Chen et al., 2012). treat the acute and chronic stages of stroke. Furthermore, a role for the gut microbiota in ischaemic injury has received attention. Finally, the immune system may play a role in remote ischaemic preconditioning-mediated neuroprotection against stroke. The development of stroke therapies sAJM589 involving organs distant to the infarct site, therefore, should not be overlooked. This review will discuss the immune mechanisms of various therapeutic strategies, surveying published data and discussing more theoretical mechanisms of action that have yet to be exploited. reduced excitotoxicity, sAJM589 neurotrophin production, and angiogenic and synaptogenic effects (Wang et al., 2018).CDK5-knockdown astrocyte cell therapy (Becerra-Calixto and Cardona-Gmez, 2017)Macrophage/microgliaIncrease ischaemic injury (M1 type) release of ROS, NO, and pro-inflammatory cytokines (e.g., TNF- and IL-12) (Chiba and Umegaki, 2013).growth factors, anti-inflammatory cytokines (e.g., IL-4), and phagocytosis of dead cells (Kanazawa et al., 2017).Minocycline (macrophage deactivator) (Lampl et al., 2007)increased leukocyte infiltration, ROS production, and BBB disruption (Chen et al., 2018a).MMPs, further exacerbating ischaemic injury. Monocytes, infiltrating 1C2 days later, function as tissue macrophages. The M1 macrophage/microglia phenotype increases ischaemic injury through the production of ROS and pro-inflammatory cytokines (TNF- and IL-1). The M1 subtype also secretes cytokines [IL-12, IL-6, transforming growth factor beta 1 (TGF-), and IL-23], which encourage the differentiation of infiltrated na?ve CD4+ T-cells into pro-inflammatory Th1 and Th17 forms. Th1 cells, through release of interferon gamma (IFN), promote the cytotoxic activity of CD8+ T-cells. Th17 cells (as well as their T-cell counterparts) further increase neutrophilic activity and enhance ischaemic through the production of IL-17. Ultimately, the pro-inflammatory milieu seen in the acute stages of ischaemic stroke sAJM589 gives way to a second, subacute anti-inflammatory phase typified by increased M2 microglial/macrophagic activity. The release of IL-10 from both glial cells and circulating Bregs encourages the generation of Tregs, a cell type that promotes neuroprotection and repair. Bregs may also play a role in the chronic immune response to stroke where they serve to reduce the effect of long-term antibody-mediated neurotoxicity. Therapeutic Strategies Targeting Astrocytes and Microglia Astrocytes undergo numerous changes post-ischaemia, including rapid swelling, increased intracellular calcium signalling, and upregulated expression of glial fibrillary acidic protein (GFAP) (Petrovic-Djergovic et al., 2016). The astroglial response begins in the infarct site as early as 4 h post-stroke, reaching peak activity around day 4 (Kim et al., 2016). Although this reactive gliosis contributes to long-term healing, the sAJM589 initial formation of the glial scar is thought to be detrimental. The scar acts as both a physical and chemical barrier to axonal re-growth, preventing reinnervation (Barreto et al., 2011). Several studies have shown that decreased astrogliosis correlates with reduced infarct size (reviewed in Barreto et al., 2011). Separate research has highlighted how astrocytes can play a similarly detrimental role in AIS as traditional leukocytes, increasing interest in immunomodulatory strategies targeting these cells. Astrocytes have been shown to express various pro-inflammatory mediators in the acute phase including cytokines, chemokines, and inducible Serpine1 nitric oxide synthase (iNOS) (Dong and Benveniste, 2001). Astrocyte-derived IL-15, for example, augments cell-mediated immunity post-stroke, promoting ischaemic injury (Roy-OReilly and McCullough, 2017). More recent work, however, points to astrocytes as promising therapeutic targets for neuroprotection and neurorestoration (Liu and Chopp, 2016). Fundamentally, the glial scar divides the site of injury from surrounding viable tissue, hindering infarct growth. During the acute phase, astrocytes also limit neuronal cell death by reducing excitotoxicity and releasing neurotrophins (Liu and Chopp, 2016). Finally, astrocytes contribute to the chronic processes of angiogenesis, neurogenesis, and synaptogenesis (Wang et al., 2018). As for many other immune targets in AIS, the manipulation of the astrocytic response may involve a combination of pharmacological [e.g., cyclin-dependent kinase 5 (CDK5) inhibitors] and cell-based therapies (Becerra-Calixto and.