Lu, Hsueh-Chung (2017-07). The Role of Myeloid STAT3 in Experimental Autoimmune Encephalomyelitis and Postnatal Brain Development. Doctoral Dissertation.
Thesis
Multiple sclerosis (MS) is a debilitating disease characterized by demyelination and neurodegeneration in the CNS. Both activated microglia and infiltrating myeloid cells are thought to contribute to disease progression of experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS. Signal transducer and activator of transcription 3 (STAT3) regulates multiple cellular functions including cell differentiation, survival, and inflammation, and is a critical signaling molecule for the interleukin-6 family of cytokines. Additionally, not only Stat3 is a risk factor for MS, but its increased phosphorylation has been detected in the MS patient myeloid cells. To investigate the role of STAT3 in myeloid cells and neuroinflammation, we generated myeloid STAT3-deficient mice (LysMcre/Stat3^fl/fl) and investigated their susceptibility to MOG35?55-induced EAE. Whereas Stat3^fl/fl control mice developed typical symptoms of EAE, LysMcre/Stat^3fl/fl mice rather resistant to EAE and exhibited diminished antigen-specific helper T-cell responses in the periphery. Splenic myeloid cells isolated from immunized LysMcre/Stat3^fl/fl mice exhibited impaired antigen-presenting and co-stimulatory functions. In contrast to active EAE, LysMcre/Stat3^fl/fl mice were partially susceptible to EAE induced by adoptive transfer of encephalitogenic T-cells, suggesting the importance of myeloid STAT3 in differentiation of helper T-cells during the initiation phase of EAE. Consistent with these findings, mice with STAT3 inactivated in microglial cells were indistinguishable from control mice in MOG35?55-induced EAE, suggesting that microglial STAT3 signaling does not play a critical role in EAE. We also investigated the role of microglial STAT3 on brain development and behaviors. Our preliminary investigation indicated that neonatal inactivation of microglial STAT3 signaling resulted in a transient reduction of microglial number at the second postnatal week, although the microglial population was largely recovered by P30. In addition, the Cx3cr1creER/Stat3^fl/fl mice exhibited altered marble burying behaviors. These results suggest that microglial STAT3 signaling plays important roles in normal postnatal brain development and that transient perturbation of microglial functions may have long-term functional consequences. In summary, this study highlights the importance of STAT3-dependent pathways in myeloid cells in the development of autoimmunity during EAE, as well as STAT3 in microglia in postnatal brain development and behaviors.
ETD Chair
Li, Jianrong Professor, Neurobiology and Neuroimmunology, Veterinary Integrative Biosciences
