Our current research is focused on the function of dendritic cells (DCs) and macrophages as key immune sentinels that initiate and modulate immunity, inflammation and tolerance. Manipulation of these cells holds promise as a potent immunotherapy tool for many diseases with an immune component, including infectious diseases, autoimmune diseases, cardiovascular diseases (CVD) and cancer. Some of our main current aims are:
- Explore the molecular pathways controlling trained immunity (TI) in macrophages and the role of TI in atherosclerosis (AT). TI is an emerging concept for a prolonged hyperactivation of the innate immune system after exposure to certain stimuli, leading to an augmented immune response to a secondary stimulus. We have previously established new mechanisms that control TI (Saz-Leal et al., Cell Rep. 2018). While this can be beneficial for host defense against invading pathogens, as we have recently applied to viral infections including COVID-19 (del Fresno et al. Front. Immunol. 2019), non-resolving inflammation and long-term over-activation of the innate immune system by TI may underlie vascular inflammation and AT. We are addressing molecular pathways that control TI and investigating the links with AT.
- Unravel novel immunometabolic mechanisms controlling DC and macrophage function and their relevance in physiopathology. We are investigating the effects of sensing non-self and damaged-self on the metabolism of myeloid cells. Our results in the emerging field of immunometabolism support that innate sensing leads to relevant metabolic reprogramming with impact in myeloid cell function, which affects the response of macrophages to infection or their proinflammatory state that contributes to obesity-related pathology (Garaude et al. Nat Immunol. 2016; Acín-Pérez, Iborra et al. Nat. Metab. 2020). Thus, the modulation of mitochondrial metabolism and dynamics is a new level of intervention for immunotherapy strategies. We will focus on the mitochondrial metabolic adaptations in DCs and macrophages in response to tissue and microorganism-derived signals and their impact in their function. From this knowledge, we aim to develop novel strategies for manipulation of DC and macrophage metabolism with impact in their function, which can be potentially relevant for immunotherapy of CVD and other diseases with an immune component.
- Investigate the gut microbiota and its related metabolites in the progression of atherosclerosis Current evidence suggests that microbiota may affect atherogenesis. However, there is notable controversy in the specific association of gut-derived metabolites and gut microbiota taxa with AT. We hypothesize that there are unidentified gut microbiota-related metabolites and gut microbiota patterns that affect the development of AT, through their effects on host metabolism, gut barrier and inflammation. We aim to: 1) Understand the contribution of the microbiota to the development of AT through the analysis of gut microbiota-derived metabolites and taxa associated with AT; 2) Assess the diagnostic/prognostic potential of microbial metabolites as markers of AT by integrating data from plasma metabolites, gut microbiota and lifestyle from three cohorts of human volunteers, two with subclinical AT and the other with more advanced AT; 3) Address the cellular and molecular mechanisms of action of a promising microbiota-derived metabolite, which we have found not only associated with AT, but also as a causal factor for the development of AT in our preliminary data. We will specifically focus on its function in macrophages and the causal effect in the development of AT; 4) Explore the therapeutic potential of the intervention in the receptor and signaling axis by which this microbiota-derived metabolite causes AT pathogenesis. The identification of novel specific profiles of gut microbiota and their plasma metabolites that are associated with active AT in the context of low-grade systemic inflammation has potential to provide more accurate diagnostic/prognostic biomarkers for AT. Moreover, deciphering potential causality and the cellular and molecular mechanisms of action of these microbiota-derived metabolites could unveil innovative targets for AT therapy.