Astrocytes are activated in experimental autoimmune encephalomyelitis (EAE) and have been suggested to either aggravate or ameliorate EAE. However, the mechanisms leading to an adverse or protective effect of astrocytes on the course of EAE are incompletely understood. To gain insight into the astrocyte-specific function of gp130 in EAE, we immunized mice lacking cell surface expression of gp130, the signal-transducing receptor for cytokines of the IL-6 family, with myelin oligodendrocyte glycoprotein35–55 peptide. These glial fibrillary acid protein (GFAP)-Cre gp130fl/fl mice developed clinically a significantly more severe EAE than control mice and succumbed to chronic EAE. Loss of astrocytic gp130 expression resulted in apoptosis of astrocytes in inflammatory lesions of GFAP-Cre gp130fl/fl mice, whereas gp130fl/fl control mice developed astrogliosis. Astrocyte loss of GFAP-Cre gp130fl/fl mice was paralleled by significantly larger areas of demyelination and significantly increased numbers of CD4 T cells in the CNS. Additionally, loss of astrocytes in GFAP-Cre gp130fl/fl mice resulted in a reduction of CNS regulatory Foxp3+ CD4 T cells and an increase of IL-17–, IFN-γ–, and TNF-producing CD4 as well as IFN-γ– and TNF-producing CD8 T cells, illustrating that astrocytes regulate the phenotypic composition of T cells. An analysis of mice deficient in either astrocytic gp130– Src homology region 2 domain-containing phosphatase 2/Ras/ERK or gp130–STAT1/3 signaling revealed that prevention of astrocyte apoptosis, restriction of demyelination, and T cell infiltration were dependent on the astrocytic gp130–Src homology region 2 domain-containing phosphatase 2/Ras/ERK, but not on the gp130–STAT1/3 pathway, further demonstrating that gp130-dependent astrocyte activation is crucial to ameliorate EAE.

Water buffalo (Bubalus bubalis) is broadly classified into river and swamp categories, but it remains disputed whether these two types were independently domesticated, or if they are the result of a single domestication event. In this study, we sequenced the mitochondrial D-loop region and cytochrome b gene of 217 and 80 buffalo respectively from eight breeds/locations in northern, north-western, central and southern India and compared our results with published Mediterranean and swamp buffalo sequences. Using these data, river and swamp buffalo were distinguished into two distinct clades. Based upon the existing knowledge of cytogenetic, ecological and phenotypic parameters, molecular data and present-day distribution of the river and swamp buffalo, we suggest that these two types were domesticated independently, and that classification of the river and swamp buffalo as two related subspecies is more appropriate.

Single-nucleotide polymorphisms in the tumor necrosis factor, alpha-induced protein 3 gene, which encodes the ubiquitin-modifying protein A20, are linked to susceptibility to multiple sclerosis (MS), a demyelinating autoimmune disease of the central nervous system (CNS). Since it is unresolved how A20 regulates MS pathogenesis, we examined its function in a murine model of MS, namely experimental autoimmune encephalomyelitis (EAE). Deletion of A20 in neuroectodermal cells (astrocytes, neurons, and oligodendrocytes; Nestin-Cre A20 mice) or selectively in astrocytes (GFAP-Cre A20 mice) resulted in more severe EAE as compared to control animals. In Nestin-Cre A20 and GFAP-Cre A20 mice demyelination and recruitment of inflammatory leukocytes were increased as compared to A20 control mice. Importantly, numbers of encephalitogenic CD4 T cells producing interferon (IFN)-γ, interleukin (IL)-17, and granulocyte-macrophage colony-stimulating factor (GM-CSF), respectively, as well as mRNA production of IFN-γ, IL-17, tumor necrosis factor (TNF), GM-CSF, IL-6, CXCL1, CCL2, and CXCL10 were significantly increased in spinal cords of Nestin-Cre A20 and GFAP-Cre A20 mice, respectively. Compared to A20-sufficient astrocytes, A20-deficient astrocytes displayed stronger activation of nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) in response to TNF, IL-17, and GM-CSF, and of signal transducer and activator of transcription 1 (STAT1) upon IFN-γ stimulation. Due to NF-κB and STAT1 hyperactivation, A20-deficient astrocytes produced significantly more chemokines in response to these key encephalitogenic cytokines of autoimmune CD4 T cells resulting in an amplification of CD4 T cell recruitment to the CNS. Thus, astrocytic A20 is an important inhibitor of autoimmune-mediated demyelination in the CNS.

Cerebral malaria is a life-threatening complication of malaria caused by the parasite Plasmodium falciparum. The growing problem of drug resistance and the dearth of new antiparasitic drugs are a serious threat to the antimalaria treatment regimes. Studies on humans and the murine model have implicated the disruption of the blood-brain barrier (BBB) in the lethal course of the disease. Therefore, efforts to alleviate the BBB dysfunction could serve as an adjunct therapy. Here, we review the mechanisms associated with the disruption of the BBB. In addition, we discuss the current, still limited, knowledge on the contribution of different cell types, microparticles, and the kynurenine pathway in the regulation of BBB dysfunction, and how these molecules could be used as potential new therapeutic targets. Cerebral Malaria-Clinical Significance and the Differences between Murine and Human Studies Cerebral malaria (CM) is a severe neurological syndrome of human malaria caused by the parasite Plasmodium falciparum (Pf) affecting mainly children in sub-Saharan Africa and adults in Asia. The complications of CM include clouding of consciousness, cerebral seizures, and coma, and may lead to the death of the infected individual. According to the 2018 WHO World Malaria Report for 2017, 435 000 patients died of malaria, with CM accounting for 90% of the deaths. About a quarter of surviving patients suffer from long-term neurological and cognitive deficits such as behavioral abnormality, epilepsy, and impaired motor functions [1,2]. Over the years, quinine and artemisinin compounds (see Glossary) have been used for the treatment of severe malaria. The use of these drugs has led to the emergence of resistant strains [3,4]. The problem of drug resistance is ever growing, and novel therapeutic strategies need to be developed, particularly those targeting the host or host-pathogen interaction. Understanding the underlying mechanisms leading to the development of CM would aid in the identification of potential new therapeutic targets. One major limitation of human CM studies is that a detailed analysis of the intracerebral pathogenesis and pathology can be conducted mainly postmortem. Therefore, CM is experimentally studied using a mouse model known as experimental cerebral malaria (ECM). Although Plasmodium berghei ANKA (PbA)-induced ECM recapitulates some of the features of human CM, the disease pathology differs considerably. While human CM is characterized by sequestration of infected red blood cells (iRBCs) to the cerebral microvasculature, with minute inflammatory changes in the brain, murine ECM shows little or no intracerebral sequestration of iRBCs but a prominent proinflammatory cytokine response in the brain. Moreover, human postmortem reports revealed no intracerebral accumulation of CD8 + T cells, whereas intracerebral accumulation of CD8 + T cells is essential for the development of ECM (reviewed in detail by White et al. [5]). These differences need to be considered while translating murine studies to human malaria....