Areas of investigation/research focus
My group is interested in elucidating pathways regulating immune cell function and how their alterations affect ageing and neurodegenerative diseases. In particular, we are interested in understanding the function of the voltage-gated proton channel HVCN1 in immune responses, as well as signalling pathways that regulate inflammation in microglia (summary in Fig. 1).
The voltage-gated proton channel HVCN1 in immune responses
There is only one mammalian voltage-gated proton channel, HVCN1. It works to relieve intracellular acidification and membrane depolarization, letting protons out of the cell following their chemical gradient. In doing so, it sustains the production of reactive oxygen species (ROS) by the enzyme NADPH oxidase (Fig. 2). We were the first to describe HVCN1 role in regulating B cell responses (Capasso et al, Nat Immunol, 2010). HVCN1 loss causes a strong impairment of antibody responses, due to reduced B Cell Receptor signaling. This is due to diminished ROS production by the NADPH oxidase: fewer ROS mean they are no longer able to oxidase and therefore inhibit phosphatases involved in B Cell Receptor signalling. We also described a splicing variant of HVCN1, shorter at the N-terminus, which is able to mediate larger currents and it is upregulated in circulating B cell malignancies such as Chronic Lymphocytic Leukaemia (Hondares et al., PNAS, 2014). Nonetheless, proton channels in B cell malignancies appear to play multiple roles, as we describe in a manuscript in preparation. In myeloid cells, HVCN1 also sustains NADPH oxidase activity, however, its role in cells implicated in the pathogenesis of Alzheimer’s disease, such as microglia and neutrophils, remains to be elucidated. We combine in vivo and in vitro studies to elucidate the impact of HVCN1 loss on this devastating neurodegenerative disease, in order to assess its potential as a therapeutic target.
Signaling pathways regulating inflammation in aged microglia
Microglia are the immune cells of the brain. They play important roles in neuronal cell homeostasis but also contribute to disease pathology in neurodegenerative diseases. While studying alterations in signaling pathways in aged microglia, we discovered an upregulation of the mTORC1 pathway, especially its regulation of protein synthesis. Indeed, during an inflammatory response, aged microglia synthesize greater amounts of inflammatory mediators, such as cytokines and immune receptors (Keane*, Antignano* et al., JCI, 2021). Genetic inhibition of mTORC1 signaling led to decreased inflammation because of reduced protein mediators, despite their mRNA expression levels being higher. Surprisingly, mTORC1 inhibition appeared to have a rather specific effect on translation of the inflammatory response, rather than mRNA translation overall. Based on these findings, we are now exploring the specificity of mTORC1 regulation over the microglia translatome in ageing and other inflammatory processes that are relevant to neurodegeneration.