Our project focuses on a thorough, innovative and integrated approach to mechanistically understand chronicity of inflammation, including metabolic inflammation. To this end, we focus on: (a) Local inflammatory mechanisms at the tissue level, especially in the adipose tissue and liver, in the context of obesity-related metabolic-inflammatory disease, such as metabolic syndrome and MASLD, and (b) Systemic mechanisms involving induction of maladaptive trained innate immunity (TII) that could also contribute to inflammatory comorbidities.
We use models of inflammation and inflammatory disease; we also use models of diet-induced obesity and diet-induced liver disease that allow us to study dysmetabolism-related inflammation of metabolic organs (adipose tissue and liver) and systemic inflammation.
(I) Local mechanisms: In chronic metabolic inflammation, there is an imbalance between activation of inflammatory cells, especially myeloid cells, and anti-inflammatory processes contributing to termination of inflammation. Metabolic signals in the obese adipose tissue and liver microenvironment shape the function of multiple cells, including immune cells, as well as non-immune tissue cells, in part via alterations in their cellular metabolism. We study metabolic pathways and their role in inflammatory cell activation and regulation of inflammation, including metabolic organ inflammation.
(II) Systemic mechanisms via maladaptive TII: Maladaptive TII involves long-term adaptations of innate immune cells that acquire higher capacity for inflammatory responses. Maladaptive TII may be initiated at the level of hematopoietic progenitors of innate immune cells in the bone marrow, via sustained epigenetic alterations, thereby potentially driving enhanced production of myeloid cells with stronger inflammatory capacity, hence, further reinforcing a feed-forward loop of perpetual inflammation that drives systemic inflammation chronicity. We pursue the hypothesis that maladaptive TII facilitates chronicity of inflammation, including metabolic inflammation, as well as promotes emergence of inflammatory comorbidities. In this context, we have also found that clonal hematopoiesis, associated with mutations in the epigenetic regulator DNA methyltransferase 3A, triggers inflammation and higher inflammatory bone loss, in a manner that has some similarities to maladaptive bone marrow-mediated TII. Moreover, we study new facets of maladaptive TII in the context of inflammation; such aspects are studied also under conditions of diet-induced obesity and metabolic dysregulation in order to understand how metabolic dysfunction-induced maladaptive TII could drive inflammation and enhanced severity of inflammatory comorbidities.
