8A). increase in macrophage/microglia and neutrophil recruitment in GFAPcre p38/mice compared to p38fl/fl controls. Together, these studies provide important insights into the crucial Rabbit Polyclonal to SYTL4 role of p38 signaling in astrocyte immune activation. Astrocytes are the most abundant glial cell type in the CNS. They perform essential regulatory functions contributing to the maintenance of CNS homeostasis, including extracellular glutamate uptake1, K+and H+buffering2, energy metabolism3, synaptic transmission4, and microcirculation regulation5,6. The CNS is usually a relatively immune privileged compartment due to the lack of lymphatic drainage and unique characteristics of its vasculature. The blood brain barrier (BBB) regulates CNS microcirculation and consists of perivascular astrocytic endfeet constituting the neurovascular unit together with endothelial cells, pericytes and microglia. Disruption of the 2C-C HCl integrity of the BBB is one of the prominent pathological changes seen after CNS injury, and is induced by complex molecular mechanisms regulated by cytokines, chemokines, nitric 2C-C HCl oxide, adhesion molecules and matrix metalloproteinases (MMPs)7,8that interact with components of the neurovascular unit. In particular, astrocytes in response to CNS injury exhibit a pathological hallmark termed as reactive astrogliosis. Studies of reactive astrocyte elimination suggest that astroglial scar formation ameliorates widespread tissue damage9,10, but detrimental effects by reactive astrocytes in inhibiting oligodendrocyte progenitor cell (OPC) migration and remyelination have also been reported11,12. Therefore, the outcome of reactive astrogliosis contributing to CNS neuropathology remains controversial. In response to inflammatory stimuli, astrocytes also produce proinflammatory cytokines and chemokines13,14,15,16. Studies suggest that astrocyte-derived TNF and IL-1 exacerbate inflammatory responses by inducing BBB disruption through paracrine effects on endothelial cells17,18,19. Moreover, astrocytes are also implicated to be a major source of crucial chemokines involved in BBB disruption and leukocyte recruitment during CNS injury14,20. In particular, monocyte chemotaxis induced by CCL2 results in BBB breakdown by the downregulation of endothelial tight junction proteins21. CXCL10 promotes T lymphocyte infiltration into the CNS parenchyma22, whereas CXCL1 facilitates the transmigration of neutrophils across the BBB23. Taken together, studies on reactive astrogliosis and its regulation of immune cell trafficking suggest a significant yet controversial role of astrocytes during CNS inflammatory injury. It remains much debated as to whether immune activation 2C-C HCl of astrocytes can facilitate or exacerbate the outcome of CNS injury, and the definitive role of astrocytes contributing to CNS neuropathology remains to be decided. The mitogen-activated protein kinase (MAPK) family transduces signals from the cell membrane to the nucleus in response to a wide variety of stimuli24. MAPK family members are serine/threonine protein kinases belonging to (1) p38 MAPKs, (2) extracellular signal-related kinases 1 and 2 (ERK1/2), and (3) Jun amino-terminal kinases (JNKs)25,26,27. p38 MAPK family members (p38, p38, p38 and p38) are involved in cell cycle regulation, apoptosis, cell development, proliferation and inflammatory responses28,29,30,31,32. Among these, p38 is considered to be a central regulator of an inflammatory response in multiple cell types33,34. Downstream substrates of p38 include transcription factors and protein kinases, leading to divergent signaling cascades that dictate cellular responses to stress and inflammation35. Pharmacological studies using p38 MAPK inhibitors indicated that astrocytes upregulate TNF and IL-1 through a p38-mediated pathway36,37. Through a feedback mechanism, downstream effects of TNF and IL-1 promote subsequent upregulation of astrocyte-derived chemokines CCL2, CCL5 CXCL2, CXCL8 and CXCL1015,38,39. Although an essential role of p38 in the astrocyte immune responses has been suggested inin vitrostudies using chemical inhibitors37,40,41, these inhibitors are not particularly specific and can also inhibit p38 and other enzymes. Therefore, the definitive role of p38 in the production of specific cytokines and chemokines in astrocytes has not been examined. Moreover, administration of p38 MAPK inhibitorsin vivoalso exhibits general therapeutic effects on CNS injury models42,43,44. However, due to the complexity of thein vivoCNS inflammation involving microglia, astrocytes and infiltrating leukocytes, there is insufficient information with regard to the cell-type specific immune response downstream of p38 signaling. Although astrocytes are capable of performing immunological functions during CNS injury, no studies have delineated the specific role of.