title: Astrocytic TGF-β signaling limits inflammation and reduces neuronal damage during central nervous system Toxoplasma infection.
abstract: The balance between controlling infection and limiting inflammation is particularly precarious in the brain because of its unique vulnerability to the toxic effects of inflammation. Astrocytes have been implicated as key regulators of neuroinflammation in CNS infections, including infection with Toxoplasma gondii, a protozoan parasite that naturally establishes a chronic CNS infection in mice and humans. In CNS toxoplasmosis, astrocytes are critical to controlling parasite growth. They secrete proinflammatory cytokines and physically encircle parasites. However, the molecular mechanisms used by astrocytes to limit neuroinflammation during toxoplasmic encephalitis have not yet been identified. TGF-β signaling in astrocytes is of particular interest because TGF-β is universally upregulated during CNS infection and serves master regulatory and primarily anti-inflammatory functions. We report in this study that TGF-β signaling is activated in astrocytes during toxoplasmic encephalitis and that inhibition of astrocytic TGF-β signaling increases immune cell infiltration, uncouples proinflammatory cytokine and chemokine production from CNS parasite burden, and increases neuronal injury. Remarkably, we show that the effects of inhibiting astrocytic TGF-β signaling are independent of parasite burden and the ability of GFAP(+) astrocytes to physically encircle parasites.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305; Neurosciences Graduate Program, Stanford Neurosciences Institute, Stanford University, Stanford, CA 94305;
authors.forename: Egle
authors.initials: E
authors.lastname: Cekanaviciute
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA 94305; BIO5 Institute, University of Arizona, Tucson, AZ 85721;
authors.forename: Hans K
authors.initials: HK
authors.lastname: Dietrich
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305;
authors.forename: Robert C
authors.initials: RC
authors.lastname: Axtell
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305;
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Williams
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305;
authors.forename: Riann
authors.initials: R
authors.lastname: Egusquiza
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305;
authors.forename: Karen M
authors.initials: KM
authors.lastname: Wai
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305; Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA 94305; BIO5 Institute, University of Arizona, Tucson, AZ 85721; Department of Neurology, University of Arizona, Tucson, AZ 85721; Department of Immunobiology, University of Arizona, Tucson, AZ 85721; and marion.buckwalter@stanford.edu akoshy@email.arizona.edu.
authors.forename: Anita A
authors.initials: AA
authors.lastname: Koshy
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305; Department of Neurosurgery, Stanford University, Stanford, CA 94305 marion.buckwalter@stanford.edu akoshy@email.arizona.edu.
authors.forename: Marion S
authors.initials: MS
authors.lastname: Buckwalter
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D018925:Chemokines / Q000235:genetics / Q000276:immunology; D005904:Glial Fibrillary Acidic Protein; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology; D009474:Neurons / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014122:Toxoplasma / Q000235:genetics / Q000276:immunology*; D016781:Toxoplasmosis, Cerebral / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D018925:Chemokines; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D016212:Transforming Growth Factor beta; C528900:glial fibrillary astrocytic protein, mouse