Regulation of autoimmune neuroinflammation by stress-responsive genes

Dissertation presented to obtain the Ph.D degree in Biology

Inflammation is a protective response generated by innate immune cells, upon infection and/or tissue injury, and aims at clearing the source of infection or noxious stimuli. It is required for activation of adaptive immunity. Inflammation has several layers of regulation in order to minimize the degree of tissue damage. Antigen-presenting cells (APC) constitute one layer of regulation as they initiate the activation of T helper (TH) cells, bridging innate and adaptive immunity. The TH cell response generated is usually protective, although in certain circumstances, that are not completely understood, can also become pathological, as occurs in multiple sclerosis (MS) and in its mouse model, experimental autoimmune encephalomyelitis (EAE). Thus, mechanisms restraining TH cell activation and/or reactivation should prevent the pathogenesis of autoimmune neuroinflammation. In this Thesis we describe two of such mechanisms: one controlled by the transcription factor NF-E2-related factor 2 (Nrf2) and another controlled by one of its downstream genes Heme oxygenase-1 (Hmox1), which encodes the enzyme HO-1. Nrf2 is a transcription factor that regulates cellular responses to oxidative stress, while HO-1 catabolizes heme into carbon monoxide (CO), iron, and biliverdin. Both, Nrf2 and HO-1 have been implicated in dampening inflammatory reactions, including autoimmune neuroinflammation. The aim of this Thesis was to understand the role(s) of Nrf2, and its downstream gene Hmox1, in the regulation of autoimmune neuroinflammation. For this, we studied the role of Nrf2 and Hmox1 expression in the pathogenesis of EAE. Further, we investigated the impact of pharmacological induction of HO-1 expression and exogenous CO administration from a therapeutic point of view. (...)

The work presented on this Thesis has been funded by the fellowship SFRH/BD/21558/2005 from FCT