Final Report Summary - ERSTRESS (Role of Endoplasmic Reticulum Stress in dendritic cells and immune-mediated lung diseases)
The purpose of this project is to unravel the role of ER stress pathways in the immune response leading to lung diseases like asthma, and smoking associated chronic obstructive pulmonary disease (COPD). These are very common diseases that are a heavy burden on patients and society. The project was initiated based on initial observations that aberrations in genes that control the process of ER stress (a biological response of cells to accumulations of improperly folded proteins inside the cells) were associated with asthma, particularly when there was exposure to cigarette smoke.
To interrogate this, we have generated a lot of new tools, in which key target genes of the ER stress pathway were specifically inactivated in dendritic cells or other immune cells. These tools have been employed in asthma models and we have found remarkable effects of ER stress pathways on the functioning of immune cells. We found that a particular subset of dendritic cells has signs of spontaneous ER stress, even in the steady state, unmanipulated situation. We have performed a fine-grained analysis of these DCs, and found that a transcription factor called Xbp1 tightly controls another enzyme IRE to maintain DC homeostasis and DC function as antigen presenting cells. This highly innovative pathway could be exploited for better vaccine design.
We have also found that the basic rate of protein translation varies massively between DC subsets in different tissues, explaining why DC subsets in different tissues might react differently when faced with external stress such as oxidative stress.
We have also zoomed in on a new STE20 kinase, involved in regulating ER stress and found it to be a crucial regulator of immune cell function in DCs and B cells. Additionally, we made the serendipitous finding that this Ste20 kinase also controls metabolism at a cellular and organismal levels. This exciting new molecule has been the start of a new drug development program in the host institute. The aim is to now make new drugs targeting this kinase.
To interrogate this, we have generated a lot of new tools, in which key target genes of the ER stress pathway were specifically inactivated in dendritic cells or other immune cells. These tools have been employed in asthma models and we have found remarkable effects of ER stress pathways on the functioning of immune cells. We found that a particular subset of dendritic cells has signs of spontaneous ER stress, even in the steady state, unmanipulated situation. We have performed a fine-grained analysis of these DCs, and found that a transcription factor called Xbp1 tightly controls another enzyme IRE to maintain DC homeostasis and DC function as antigen presenting cells. This highly innovative pathway could be exploited for better vaccine design.
We have also found that the basic rate of protein translation varies massively between DC subsets in different tissues, explaining why DC subsets in different tissues might react differently when faced with external stress such as oxidative stress.
We have also zoomed in on a new STE20 kinase, involved in regulating ER stress and found it to be a crucial regulator of immune cell function in DCs and B cells. Additionally, we made the serendipitous finding that this Ste20 kinase also controls metabolism at a cellular and organismal levels. This exciting new molecule has been the start of a new drug development program in the host institute. The aim is to now make new drugs targeting this kinase.