Local and systemic mechanisms for metabolic inflammation chronicity

Chronic inflammation underlies several diseases and is a common basis of multiple comorbidities. In obesity, chronic inflammation of the adipose tissue (AT) and liver contributes to the metabolic syndrome and related metabolic-inflammatory pathologies. Here, we propose a thorough and innovative approach to revolutionize understanding of metabolic inflammation chronicity. We will address both local (at the respective tissue level) and systemic mechanisms, involving the novel principle of trained innate immunity (TII) and inflammatory adaptation of the bone marrow (BM). (i) Local: In chronic metabolic inflammation, there is an imbalance between chronic accumulation/activation of inflammatory cells and resolution of inflammation (RoI) in favor of the former. Based on our recent findings regarding integrin-dependent chronic macrophage retention in the obese AT and that Developmental endothelial locus-1 promotes RoI, we will here identify novel pathways towards counter-acting chronicity of metabolic inflammation and facilitating its resolution and test their therapeutic efficacy. (ii) Systemic: Systemic metabolic/inflammatory feedback to the BM may trigger long-term adaptations of hematopoietic progenitors, fueling a feed-forward loop of perpetual inflammation. Following our discovery that TII is initiated in the BM, we will pursue the hypothesis that maladaptive training of BM progenitors in obesity facilitates metabolic inflammation chronicity, via generation of myeloid cells with higher potential for tissue accumulation and inflammatory activation, and promotes development of obesity-related inflammatory comorbidities. Despite apparent links, local and systemic mechanisms are mostly studied independently of each other rather than through an integrative approach, which will be followed here for the first time. Our proposal will lead to breakthrough concepts in metabolic inflammation chronicity and to novel therapeutic strategies for metabolic-inflammatory pathologies.