Restrained Th17 response and myeloid cell infiltration into the central nervous system by human decidua-derived mesenchymal stem cells during experimental autoimmune encephalomyelitis

Background: Multiple sclerosis is a widespread inflammatory demyelinating disease. Several immunomodulatory therapies are available, including interferon-β, glatiramer acetate, natalizumab, fingolimod, and mitoxantrone. Although useful to delay disease progression, they do not provide a definitive cure and are associated with some undesirable side-effects. Accordingly, the search for new therapeutic methods constitutes an active investigation field. The use of mesenchymal stem cells (MSCs) to modify the disease course is currently the subject of intense interest. Decidua-derived MSCs (DMSCs) are a cell population obtained from human placental extraembryonic membranes able to differentiate into the three germ layers. This study explores the therapeutic potential of DMSCs. Methods: We used the experimental autoimmune encephalomyelitis (EAE) animal model to evaluate the effect of DMSCs on clinical signs of the disease and on the presence of inflammatory infiltrates in the central nervous system. We also compared the inflammatory profile of spleen T cells from DMSC-treated mice with that of EAE control animals, and the influence of DMSCs on the in vitro definition of the Th17 phenotype. Furthermore, we analyzed the effects on the presence of some critical cell types in central nervous system infiltrates. Results: Preventive intraperitoneal injection of DMSCs resulted in a significant delay of external signs of EAE. In addition, treatment of animals already presenting with moderate symptoms resulted in mild EAE with reduced disease scores. Besides decreased inflammatory infiltration, diminished percentages of CD4+IL17+, CD11b+Ly6G+ and CD11b+Ly6C+ cells were found in infiltrates of treated animals. Early immune response was mitigated, with spleen cells of DMSC-treated mice displaying low proliferative response to antigen, decreased production of interleukin (IL)-17, and increased production of the anti-inflammatory cytokines IL-4 and IL-10. Moreover, lower RORγT and higher GATA-3 expression levels were detected in DMSC-treated mice. DMSCs also showed a detrimental influence on the in vitro definition of the Th17 phenotype. Conclusions: DMSCs modulated the clinical course of EAE, modified the frequency and cell composition of the central nervous system infiltrates during the disease, and mediated an impairment of Th17 phenotype establishment in favor of the Th2 subtype. These results suggest that DMSCs might provide a new cell-based therapy for the control of multiple sclerosis.This work was sponsored by grants from Acción Estratégica en Salud (PI13/00297 and PI11/00581), the Neurosciences and Aging Foundation, the Francisco Soria Melguizo Foundation, Octopharma, and Parkinson Madrid (PI2012/0032).S

Transgenic inhibition of astroglial NF-κB restrains the neuroinflammatory and neurodegenerative outcomes of experimental mouse glaucoma

Background Glia-driven neuroinflammation promotes neuron injury in glaucoma that is a chronic neurodegenerative disease of the optic nerve and a leading cause of irreversible blindness. Although therapeutic modulation of neuroinflammation is increasingly viewed as a logical strategy to avoid inflammatory neurotoxicity in glaucoma, current understanding of the molecular regulation of neuroinflammation is incomplete, and the molecular targets for immunomodulation remains unknown. Growing datasets pointed to nuclear factor-kappaB (NF-κB), a key transcriptional activator of inflammation, which was identified to be most affected in glaucomatous astroglia. Using a cell type-specific experimental approach, this study aimed to determine the value of astroglial NF-κB as a potential treatment target for immunomodulation in experimental mouse glaucoma. Methods Neuroinflammatory and neurodegenerative outcomes of experimental glaucoma were comparatively analyzed in mice with or without cre/lox-based conditional deletion of astroglial IκKβ, which is the main activating kinase involved in IκB degradation through the canonical pathway of NF-κB activation. Glial responses and the inflammatory status of the retina and optic nerve were analyzed by cell morphology and cytokine profiling, and neuron structure and function were analyzed by counting retinal ganglion cell (RGC) axons and somas and recording pattern electroretinography (PERG) responses. Results Analysis of glial inflammatory responses showed immunomodulatory outcomes of the conditional transgenic deletion of IκKβ in astroglia. Various pro-inflammatory cytokines known to be transcriptional targets for NF-κB exhibited decreased production in IκKβ-deleted astroglia, which included TNF-α that can induce RGC apoptosis and axon degeneration during glaucomatous neurodegeneration. Indeed, transgenic modulation of inflammatory responses by astroglial IκKβ deletion reduced neurodegeneration at different neuronal compartments, including both RGC axons and somas, and protected PERG responses. Conclusions The findings of this study support a key role for astroglial NF-κB in neuroinflammatory and neurodegenerative outcomes of experimental glaucoma and the potential of this transcriptional regulator pathway as a glial treatment target to provide neuroprotection through immunomodulation. By pointing to a potential treatment strategy targeting the astroglia, these experimental findings are promising for future clinical translation through transgenic applications to improve the treatment of this blinding disease