Mechanisms of nuclear receptor-mediated control of TH17 differntiation
Clinical Neurology; Neurosurgery and Neuroradiology
Final Report Abstract
As pharmacological activation of LXRhas been shown to ameliorate disease severity in mice during EAE, we aimed to address the impact of LXR and FXR activation on Teff versus Treg cell activation. Interestingly, activation by pharmacological ligands suppressed differentiation of CD4+ T cells both into Th1 and into Th17 cells. TGFb-induced Treg generation was significantly enhanced in the presence of agonists. Importantly, nuclear receptor activation not only enhanced the frequency of Tregs but also increased their suppressive capacity as demonstrated in a functional suppression assay. In contrast to LXR as of now the role of FXR in CNS autoimmunity has yet to be addressed. Hence our findings in the vivo set up, showinga ameliorative effect during EAE upon FXR activation are highly promising. Strikingly FXR activation led to a significant amelioration in EAE. This nuclear receptor has, as of now not been addressed in CNS autoimmunity. Taken together the ligand dependent activation shows the capability of restoring the balance between Teff and Treg responses, which identifies the nuclear receptors as a new promising target of T cell immunomodulation in MS. Based on the gathered data the project was successfully transferred from the SFB 704 to the Transregional Collaborative Research Center (CRC) with the running title “Initiating/effector versus regulatory mechanisms in Multiple Sclerosis – progress towards tackling the disease”. Our overall aim remains the characterization of nuclear receptors for their support of adaptive and innate immuneregulatory mechanisms and the resulting resolution of inflammation in the context of MS. This includes the following parts: (1) Role of nuclear receptors for restoring the balance between Treg and Teff for control of autoimmunity. (2) Role of nuclear receptors for control of macrophage activation and M2 polarization in CNS autoimmunity. (3) Reciprocal interaction between nuclear receptors and autoimmune inflammation in the course of MS.
