No abstract

SUMMARY Aicardi-Goutières syndrome (AGS), a hereditary autoimmune disease, clinically and biochemically overlaps with systemic lupus erythematosus (SLE) and, like SLE, is characterized by spontaneous type I interferon (IFN) production. The finding that defects of intracellular nucleases cause AGS led to the concept that intracellular accumulation of nucleic acids triggers inappropriate production of type I IFN and autoimmunity. AGS can also be caused by defects of SAMHD1, a 3′ exonuclease and deoxy-nucleotide (dNTP) triphosphohydrolase. Human SAMHD1 is an HIV-1 restriction factor that hydrolyzes dNTPs and decreases their concentration below the levels required for retroviral reverse transcription. We show in gene-targeted mice that also mouse SAMHD1 reduces cellular dNTP concentrations and restricts retroviral replication in lymphocytes, macrophages, and dendritic cells. Importantly, the absence of SAMHD1 triggered IFN-β-dependent transcriptional upregulation of type I IFN-inducible genes in various cell types indicative of spontaneous IFN production. SAMHD1-deficient mice may be instrumental for elucidating the mechanisms that trigger pathogenic type I IFN responses in AGS and SLE.

Repair of cartilage defects with a tissue-engineered implant yielded a consistent gross cartilage repair with a matrix predominantly composed of type II collagen up to 6 months after implantation. This initial result holds promise for the use of this unique bioreactor/tissue-engineered implant in humans.

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.