Gp130-Dependent Astrocytic Survival Is Critical for the Control of Autoimmune Central Nervous System Inflammation

Abstract

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.

Astrocytic Fas ligand expression is required to induce T‐cell apoptosis and recovery from experimental autoimmune encephalomyelitis

“…We hypothesize that astrocytes, which constitutively express FasL, may play a key role given that FasL-expressing astrocytes are in intimate contact with apoptotic T cells in EAE and can induce apoptosis of activated CD4 + T cells in vitro [21,22]. Consistently, our previous study also demonstrated that increased apoptosis of gp130-deficient astrocytes exacerbated EAE, partially due to an impaired elimination of CD4 + T cells from the CNS [23]. However, in vivo evidence confirming that astrocytic FasL is involved in the induction of CD4 + T-cell apoptosis in EAE is still lacking.…”

“…The kinetics of disease and intraspinal CD4 + T-cell numbers indicate that FasL-dependent elimination of CD4 + T cells in EAE plays a particularly protective role in the recovery phase. Noteworthy, the more severe EAE of GFAP-Cre FasL fl/fl mice cannot be attributed to the GFAP-Cre transgene, since C57BL/6 GFAPCre mice without a loxP-flanked gene develop the same course of EAE as compared to WT mice [23].…”

“…In this regard, it is of note that gp130-dependent astrocyte survival and astrogliosis are critical to restrict CNS inflammation in EAE as well as in CNS infections, i.e. Toxoplasma encephalitis [23,36]. Consistently, blocking NF-κB signaling, which is required for astrocyte activation in EAE, by tissue-specific ablation of key signaling molecules including NEMO, IKK2, and Act1 in the CNS impaired astrocytic production of inflammatory cytokines and chemokines ameliorating EAE as evidenced by decreased leukocyte infiltration and reduced demyelination [5,37,38].…”

“…injections of 200 ng pertussis toxin (Sigma), dissolved in 200 μL PBS, at the time of immunization as well as 48 h thereafter. Clinical signs of EAE were monitored daily and scored according to a scale of severity from 0 to 5 as described previously [23]. Daily clinical scores were calculated as the average of all individual disease scores within each group.…”

Astrogliosis

“…Deletion of estrogen receptor-a, but not estrogen receptor-b, selectively from astrocytes diminishes the antiinflammatory and neuroprotective effects of estrogen on autoimmune inflammation (Spence et al 2011(Spence et al , 2013. In contrast, deletion of STAT3 or its associated membrane receptor GP130, markedly increases the spread of inflammation after traumatic injury, autoimmune disease, or infection (Okada et al 2006;Drogemuller et al 2008;Herrmann et al 2008;Haroon et al 2011;Wanner et al 2013). Deletion of YLK-40/BRP-39, an astrocyte produced anti-inflammatory protein, exacerbates autoimmune disease in mice (Bonneh-Barkay et al 2012).…”