Regulation of autoimmune neuroinflammation by Hv1 proton channels

Abstract

Dysregulation of plasmacytoid dendritic cells (pDC) has been implicated in the pathogenesis of different autoimmune diseases including multiple sclerosis. The main effector function of pDCs is the secretion of type I interferon (IFN) which essentially contributes to the defense against viral infection. Alternatively, pDCs may also acquire a different activation state which is characterized by the secretion of distinct proinflammatory cytokines and the presentation of antigen. In both cases activation requires the recognition of CpG oligonucleotides by endosomal TLR9, while the nature of pDC activation, that is type I IFN secretion or antigen-presentation, depends on whether TLR9 binds its ligand in early or late endosomes, respectively. Precise regulation of endosomal function is consequently required to ensure sufficient pDC activation during the defense against pathogens, but at the same time prevent inappropriate pDC activation to maintain immune homeostasis at the steady state. Data presented in this thesis shows for the first time that pDCs express the voltage-gated proton channel Hv1 which is known to be involved in phagosomal function in other immune cells. Of note, stimulation of pDCs via TLR9 in early, but not late endosomes enhances expression of Hv1. In addition, endosomal acidification is impaired in pDCs of Hv1-deficient mice and this is accompanied by reduced secretion of IFN as well as decreased upregulation of the costimulatory molecule CD40 and secretion of proinflammatory cytokines after stimulation of TLR9 in early and late endosomes, respectively. These findings strongly suggest that Hv1 is essential for normal endosomal function and signaling in this cell type. Moreover, Hv1-deficient mice show an exacerbated disease course of experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis, which might be attributed to an impaired type I interferon response in vivo. Providing an additional possible explanation for the aggravated disease severity, the immune phenotype of Hv1-deficient mice is altered at the steady state and characterized by increased T cell activation, an altered B cell compartment and highly elevated frequencies of pDCs in lymph nodes. These results further underline the importance of Hv1 proton channels in the control of immune homeostasis and activation and establish pDCs as a promising candidate population for future research.