TNFR2 Sex Differences and EAE

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Abstract The susceptibility to Multiple Sclerosis (MS) is believed to be due in part to neuroinflammation and disease burden linked to neurodegeneration. It is well established that females have a more robust immune response than males however, neurodegeneration and disease progression are more sever in males. Thus, in the context of MS, this raises an intriguing question. Do females, by virtue of having a more robust inflammatory responses, have endogenous protection/repair mechanisms to protect the central nervous system (CNS) from inflammation induced pathology, that males do not have or that are not as effective in males? This proposal is based upon extensive preliminary and published data demonstrating that tmTNF/TNFR2 signaling in females, but not males, significantly improves motor function and reduces neuropathology in EAE by activating endogenous repair programs in neurons and oligodendrocytes. Based upon these and other results, our first experimental goal is to interrogate sex differences in tmTNF/TNFR2 induced improvements in motor function and neuropathology. Further, we have very novel pharmacological and genetic data that ligation of TNFR2 on both neurons and oligodendrocytes induce regenerative responses, through IRE1-dependent mechanisms. Based upon these and additional data our second experimental goal is to investigate the intersection between TNFR2/IRE1 signaling and to determine if the therapeutic effects of TNFR2 activation are dependent upon IRE1 activation. These goals will be tested in the following aims: Specific Aim 1: Investigate the sex-specific effects of tmTNF/TNFR2 signaling in the improvement of motor function and neuropathology. A) We will investigate the role of sex hormones in tmTNF/TNFR2 signaling in the improvement of motor function and neuropathology in male and female mice. B) We will investigate the role of sex chromosomes in tmTNF/TNFR2 signaling in the improvement of motor function and neuropathology in male and female mice. Specific Aim 2: Investigate TNFR2 induced endogenous repair mechanisms in male and female mice. A) We will interrogate TNFR2 induced endogenous repair mechanisms oligodendrocytes and determine if they are required for motor recovery in females. B) We will interrogate TNFR2 induced endogenous repair mechanisms neurons and determine if they are required for motor recovery in females, in vivo and in vitro.