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Critical role of STAT5 tetramerization in the pathogenesis of experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis
Multiple sclerosis (MS) is an immune mediated disease that predominantly impacts the central nervous system (CNS). Current MS treatments have demonstrated the ability to reduce the rate of MS relapses; however, they are not effective at preventing disease progression. Elucidating the pathways that g...
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Published in: | The Journal of immunology (1950) 2019-05, Vol.202 (1_Supplement), p.115-115.12 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | Multiple sclerosis (MS) is an immune mediated disease that predominantly impacts the central nervous system (CNS). Current MS treatments have demonstrated the ability to reduce the rate of MS relapses; however, they are not effective at preventing disease progression. Elucidating the pathways that govern the pathogenesis of MS may identify molecular mediators, which can act as novel therapeutic targets to treat MS progression. STAT5 is a transcription factor critical for the generation, activation, and function of different immune cell types. Upon activation, STAT5 can form dimers or tetramers, which have distinct functions. Using a Stat5a-Stat5b double knock-in N-domain mutant mouse strain (DKI mice), in which STAT5 dimers are functional, but STAT5 tetramers cannot be formed, we demonstrated that DKI mice developed less severe experimental autoimmune encephalomyelitis (EAE), a model of MS, compared to WT littermates. Moreover, a portion of DKI mice did not develop EAE symptoms. Flow cytometric analysis of peripheral blood revealed that during the early phase of EAE, WT and DKI mice exhibited similar levels of immune cell expansion in the periphery. However, at the peak of EAE, DKI mice had fewer immune cells in the CNS. This suggests that STAT5 tetramers promote immune cell egress to the CNS or/and immune cell expansion within the CNS. In addition, multiplex protein assays established that the expression of a pro-inflammatory cytokine and several chemokines, including IL-1α, CCL3, CCL17, and CCL22, are reduced in DKI mice compared to WT mice, which may account for the reduced disease severity observed in DKI mice. Taken together, the data suggest that STAT5 tetramers plays a multifaceted role in promoting inflammation resulting in EAE. |
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ISSN: | 0022-1767 1550-6606 |
DOI: | 10.4049/jimmunol.202.Supp.115.12 |