Molecular Immunology and Inflammation
The aim of the Molecular Immunology and Inflammation group is to uncover novel molecular mechanisms that regulate inflammation and innate immune responses. Through this, we aim to advance our understanding of the molecular aetiology of inflammatory skin diseases and other immune disorders, which ultimately may pave the way for improved treatment strategies.
Our research focuses on understanding the processes that control immune responses, with a particular focus on innate immune responses. The group studies molecular mechanisms governing inflammatory signalling and other host-defence processes during innate immune responses. Through this, we aim to understand the molecular events that on one hand protect against invading pathogens and tissue damage, but also contribute to chronic inflammation, autoimmunity and tumour development.
A central focus of our research is to elucidate the role and regulation of the ubiquitin system, which plays a central role in regulating inflammation and immune responses in the skin, gastrointestinal tract and other tissues/organs.
The ubiquitin system is an emerging drug target and through detailed studies of the molecular mechanisms underpinning ubiquitin-based immune signalling, we aim to identify ‘druggable’ molecular processes that ultimately may have clinical benefit in the treatment of skin diseases and other immune-driven pathologies.
We use biochemistry, molecular and cell biology together with mass spectrometry-based proteomics, transcriptomics, and bioinformatic analyses to uncover ubiquitin-regulated signalling processes of the innate immune system. We use genetically-altered mice to investigate the role of these ubiquitin-regulated processes in regulation of the immune system under (patho)physiological conditions.
The modification of proteins with ubiquitin, termed ubiquitination, is essential for signalling by pathogen-sensing pattern recognition receptors such as Toll-like and NOD-like receptors and cytokine receptors such as TNF receptor 1 and IL-1 receptor. Ubiquitin is assembled into polymeric ubiquitin chains by ubiquitin E3 ligases and are disassembled by deubiquitinases. These chains, depending on how they are assembled, alter the function, subcellular location, or stability of the modified protein. Lys48-linked ubiquitin chains cause proteasomal degradation of the modified protein whereas Lys63- and Met1-linked ubiquitin chains function as essential signalling scaffolds in innate immune signalling.
Current questions we are addressing include:
- How is the Met1-linked ubiquitin conjugating machinery regulated?
- What is the function of different ubiquitin chains in inflammatory signalling?
- How do ubiquitin chains influence inflammatory responses in the skin and within the tumour microenvironment?
In previous studies, we have investigated how ubiquitin controls signalling downstream of the innate immune receptor NOD2 - a bacteria-sensing receptor central for maintaining an immunological barrier in the gastrointestinal tract, and for which loss-of-function mutations predisposes to inflammatory bowel disease (IBD), a condition that increases the risk of intestinal cancer.
Our work has contributed to understanding the ubiquitin-dependent processes that control NOD2 signalling, including identifying X-linked IAP (XIAP) as an essential ubiquitin ligase for NOD2 signalling and that NOD2 responses can be attenuated by targeted the interaction between XIAP and the kinase RIPK2 using small-molecule inhibitors. More recently, our work has uncovered that signalling mediated by the linear ubiquitin chain assembly complex (LUBAC), a ubiquitin ligase that mediates signalling by most immune receptors, is regulated by the deubiquitinases OTULIN and SPATA2-CYLD.
|Berthe Katrine Fiil||Assistant Professor - Tenure Track||+4535333135|
|Chris Kedong Wang||Postdoc||+4535322323|
|Frederik Timmermann||PhD Fellow||+4535325092|
|Majken Kjær||Laboratory Technician||+4535333788|
|Malin Jessen||Research Assistant|
|Wenxin Lyu||External, Ph.d Student||+4535324658|