Role of ER stress in inflammation
The ER stress pathway allows the cell to adapt to stimuli that alter the protein folding capacity of the ER. Under homeostatic conditions this pathway may subtly modulate ER function. Stimuli that induce differentiation or physiological and infectious insults can induce acute changes in the ER stress signalling response. Defects in the ER stress pathway or potent ER stress signals may alter the balance between between the cell survival and pro-apoptotic pathways evoked during this response.
Relevance to inflammation
My work has identified that the response of innate immune cells to pathogens can be modified by the activation of cellular stress pathways. This was clearly shown by the requirement for the ER stress induced transcription factor, CHOP, in the expression of the pro-inflammatory cytokine, IL-23. We are currently embarking on a 5 year research programme funded by Arthritis UK, to investigate whether arthritis (an inflammatory condition that is highly dependent on IL-23) can be modulated by changes in the quality of the ER stress response.
The role of Thymic stromal lymphopoietin (TSLP) expression by dendritic cells.
TSLP produced by epithelial cells acts on dendritic cells (DC) to drive differentiation of TH2 cells, and is therefore important in allergic disease pathogenesis. However, we have identified that DC make significant amounts of TSLP in response to microbial products in an autocrine fashion. We have recently identified the critical signals that induce TSLP secretion and the role of TSLP in the regulation of proinflammatory cytokine expression such as IL-1beta, IL-6 and IL-23. This work has revealed a novel pathway of IL-1beta regulation. Autocrine TSLP production is likely to play a role in mDC-controlled immune responses at sites removed from epithelial cell production of the cytokine, such as lymphoid tissue.
The dynamic interaction of Chlamydia trachomatis with host cells.
Chlamydia trachomatis (CT) infection imparts a large burden on the human population, particularly amongst young adults, contributing significantly to the prevalence of sexually transmitted diseases, infertility and preventable blindness. CT is an obligate intracellular bacterium that is exquisitely adapted to manipulate the environment of the host cell. In contrast to gene expression studies, there is no information on the global protein changes that occur during the infectious process. New work in my laboratory recently funded by a MRC project grant is utilising a powerful multiplexed proteomic technique that allows the relative abundance of chlamydia and host proteins to be determined accurately over the course of the infectious life cycle in both human epithelial and dendritic cells. This approach will provide the first opportunity to interrogate the chlamydia and host protein responses in tandem and provide a dynamic insight into the chlamydia-host interaction.
Induction of inflammation by the pathogen Chlamydia trachomatis
The role of stress signals in pathogen responses was clearly emphasized by experiments using the obligate intracellular pathogen, Chlamydia trachomatis. We identified that IL-23 expression induced by this bacterial infection was dependent on both toll like receptor activation but also on the expression of ER stress proteins including CHOP. This suggests that ER stress pathways play an important role in inflammatory responses to pathogens. A recent Medical Research Council funded grant has enabled my laboratory to address some fundamental mechanistic questions regarding how chlamydia activates these cellular stress pathways.
ER stress in the atherosclerotic plaque
ER stress pathways instigated in macrophages as a result of cholesterol loading or mechanical forces play an important role in the development of the atherosclerosis plaque and aneurysm. We are currently investigating in collaboration with Ziad Mallat (Division of Cardiovascular medicine) how modulation of stress pathways may modify the induction of apoptosis and differentiation in critical cells subsets in disease development.