We also study the molecular mechanisms of inflammatory diseases driven by genetic germline or somatic mutations. Our key areas of research and research expertise include the regulation and function of the innate immune system, and the molecular and genetic mechanisms regulating the canonical and non-canonical inflammasome activation. We also study the interactions of innate immunity with commensal and pathogenic bacteria and the role of bacteria-derived lipopolysaccharides and metabolic endotoxemia in the inflammation of synovial tissue of joints and arterial wall.
Genetically driven diseases offer a unique opportunity to study and understand how genes regulate the immune system. During the recent years the number of known genetically determined autoinflammatory diseases has increased along with the realization that in patients with atypical inflammatory diseases, underlying genetic errors can be found far more common than has been previously anticipated. In addition to classical autoinflammatory diseases such as the cryopyrinopathies associated with mutations of NLRP3 inflammasome, novel disease mechanisms are emerging such as the interferonopathies and the autoinflammatory diseases associated with dysregulation of protein ubiquitylation, such as the TNFAIP3 haploinsufficiency. In our research, we aim to identify familial inflammatory diseases of unknown etiology and search from the affected patients' novel genetic mutations. When a candidate mutation is found by genetic studies, we elucidate the significance of the mutation in the disease pathogenesis and the effects of the mutation on the immunological signaling pathways and inflammasome activation, and the molecular mechanisms leading to the disease phenotype and symptoms. Together with our collaborators we have identified and studied the mechanisms of diseases caused by novel mutations in genes such as NFKB1, TNFAIP3, and the transcription factor CEBPe and have described novel disease mechanisms and disease phenotypes associated with these mutations.
Intestinal dysbiosis has been recently implicated in the pathogenesis of myriad of diseases. However, the mechanisms how intestinal dysbiosis could result in a disease pathogenesis is mostly unknown. Therefore our aim is to elucidate how bacteria derived products, in particular lipolysaccharides (LPS) activate the immune system, and the mechanisms how our body limits the proinflammatory impact of the large LPS load originating from the terminal ileum and large intestine, mouth and skin. We also search for means to target these mechanisms for therapeutic purposes. Areas of particular interest include the role of different LPS structures in immune activation in joints and in arterial wall, and the mechanisms of desensitization to lipopolysaccharides. To study the significance of metabolic endotoxemia in human diseases we take advantage of unique large cohorts of healthy persons and patients with rheumatic diseases, osteoarthritis and cardiovascular diseases.
In 2010 we described that cholesterol crystals activate the human macrophages. This study and the study by Dwuell et al. demonstrating the role of NLRP3 inflammasome in atherosclerosis in mice, linked the lipid metabolism and inflammation in the pathogenesis of atherosclerotic diseases and also paved the way to the CANTOS study, which for the first time showed that targeting cardiovascular inflammation with cananicumab, a monoclonal antibody against IL-1beta, indeed reduces cardiovascular endpoints. We have continued to study the role of inflammation in atherosclerosis. Key areas of interest include the role of inflammasome activation in endothelial cells and the role of metabolic endotoxemia as the driver of inflammation in atherosclerosis, and how these pathways could be targeted to treat cardiovascular diseases (CVD). For example, we have just completed a clinical study which assesses whether targeting inflammation with antirheumatic drug hydroxychloroquine can reduce the cardiovascular risk profile or cardiovascular endpoints in patients with a high risk of CVD.