Critical role of STAT5 tetramerizaton in the pathogenesis of experimental autoimmune encephalomyelitis
Kelly L. Monaghan1, Sarah M. Milne1, Breanne Y. Farris1, Jian-Xin Lin2, Warren J. Leonard2, Edwin C.K. Wan1
1Department of Microbiology, Immunology, and Cell Biology, and the Rockefeller Neuroscience Institute, West Virginia University School of Medicine, Morgantown, WV 26506, USA; 2Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
Multiple sclerosis (MS) is a debilitating autoimmune disease which primarily impacts the central nervous system (CNS). MS is driven by the activation of autoreactive T cells which are thought to recognize CNS-derived self-antigen. The activation of autoreactive T cells drives the expansion of local and infiltration of peripheral myeloid cells into the CNS. Elucidating the pathways that govern the pathogenesis of MS can identify molecular mediators, which can act as therapeutic targets. STAT5 is a transcription factor critical for the generation, activation, and function of immune cells. Upon activation, STAT5 will form a dimer which can further oligomerize via the N-terminal domain to form a tetramer molecule. 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 develop less severe experimental autoimmune encephalomyelitis (EAE) compared to WT littermates, and a portion of the DKI mice did not develop EAE symptoms. We found that during the early phase of the disease, WT and DKI mice demonstrate similar levels of immune cell expansion in the periphery. However, at the peak of EAE, DKI mice which develop mild disease have a similar immune cell profile in the spinal cord compared to the WT mice, whereas DKI mice which do not develop EAE have fewer immune cells in the CNS. This suggests that STAT5 tetramer promotes immune cell egress to the CNS. In addition, multiplex protein assays show that expression of several pro-inflammatory cytokines and chemokines, including CXCL1, CCL17, CCL22, CCL3 and IL-1α are reduced in DKI mice compared to WT mice, which may account for the reduced disease severity in DKI mice. Taken together, these data suggest that STAT5 tetramer plays a multifaceted role in driving neuroinflammation. Elucidating such pathways may identify novel targets for treating MS.