IFN-γ Signaling to Astrocytes Protects from Autoimmune Mediated Neurological Disability

Abstract

Demyelination and axonal degeneration are determinants of progressive neurological disability in patients with multiple sclerosis (MS). Cells resident within the central nervous system (CNS) are active participants in development, progression and subsequent control of autoimmune disease; however, their individual contributions are not well understood. Astrocytes, the most abundant CNS cell type, are highly sensitive to environmental cues and are implicated in both detrimental and protective outcomes during autoimmune demyelination. Experimental autoimmune encephalomyelitis (EAE) was induced in transgenic mice expressing signaling defective dominant-negative interferon gamma (IFN-γ) receptors on astrocytes to determine the influence of inflammation on astrocyte activity. Inhibition of IFN-γ signaling to astrocytes did not influence disease incidence, onset, initial progression of symptoms, blood brain barrier (BBB) integrity or the composition of the acute CNS inflammatory response. Nevertheless, increased demyelination at peak acute disease in the absence of IFN-γ signaling to astrocytes correlated with sustained clinical symptoms. Following peak disease, diminished clinical remission, increased mortality and sustained astrocyte activation within the gray matter demonstrate a critical role of IFN-γ signaling to astrocytes in neuroprotection. Diminished disease remission was associated with escalating demyelination, axonal degeneration and sustained inflammation. The CNS infiltrating leukocyte composition was not altered; however, decreased IL-10 and IL-27 correlated with sustained disease. These data indicate that astrocytes play a critical role in limiting CNS autoimmune disease dependent upon a neuroprotective signaling pathway mediated by engagement of IFN-γ receptors.

Silencing IFN-γ Binding/Signaling in Astrocytes versus Microglia Leads to Opposite Effects on Central Nervous System Autoimmunity

“…Therefore, silencing IFN-γ signaling in astrocytes diminishes a secondary wave of inflammatory infiltration and ensuing disease development. A recent report showed that IFN-γ signaling in astrocytes protects from autoimmune-mediated neurological disability (27), and we believe that the difference in results in our study and this report is mainly due to the different knockdown approaches used. In the report by Hindinger et al, IFN-γ signaling in astrocytes was blocked through transgenic overexpression of dominant-negative IFN-γR1 in astrocytes.…”

“…The mechanism underlying the anti-inflammatory effects of IFN-γ signaling in CNS cells is not known. A recent study showed enhanced EAE severity in a transgenic mouse model, in which IFN-γ can bind to dominant-negative IFN-γR1 but cannot initiate downstream IFN-γ signaling pathways in astrocytes (27), whereas the role of IFN-γ responsiveness in microglia in MS/EAE has not been defined. Elucidating IFN-γ binding/signaling in individual CNS cells, e.g., astrocytes and microglia, is crucial not only for our understanding of the mechanism underlying the development of MS/EAE, but also for designing a CNS- targeted therapy.…”

Intranasal delivery of FSD‐C10, a novel Rho kinase inhibitor, exhibits therapeutic potential in experimental autoimmune encephalomyelitis

“…Interferon-c signalling to astrocytes limited demyelination and down-regulated inflammation during acute EAE. 30 Exogenous administration of IFN-c decreased Th17 cells in EAE, orchestrating the number and function of Th17 cells. 31 Interestingly, Fasudil and FSD-C10 have been found to possess a potentially neuroprotective function; however, the mechanism underlying this effect is not clear.…”

Immune Privilege as an Intrinsic CNS Property: Astrocytes Protect the CNS against T-Cell-Mediated Neuroinflammation

“…The concept of immune privilege of the CNS may be weakening, but it is clear that astrocytes dampen inflammation and have beneficial, neuroprotective effects on the healthy brain. Astrocytes need activation by IFN- γ to unfold their anti-inflammatory potential, in forms such as IL-27 production [141]. Even when unable to prevent T-cell responses in the brain after prolonged provocation (e.g., by IFN- γ ), their function does not become purely detrimental.…”

“…In the presence of astrocytes, T cells upregulate CTLA-4 [107] which upon ligation of B7 molecules induces a stop of proliferation and anergy of the T cells. (3) IFN- γ produced by invading T cells stimulates astrocytic IL-27 production which suppresses Th17 cells [120, 121, 141]. (4) During sustained T-cell-mediated inflammation, IFN- γ secreted by T cells activates astrocytes to gain the ability to present antigen on MHC-II and costimulate T cells.…”