Overall theme: Macrophages play a critical role in inflammatory diseases via the elaboration of cytokines. We have observed that macrophages undergoing an intracellular ER stress response called the “Unfolded Protein Response” produce greatly augmented levels of cytokines in response to infectious stimuli such as Toll-like receptors. The Unfolded Protein Response has been implicated in such diverse processes as viral infection, cancer, neurodegenerative disease, autoimmune diseases, diabetes and cardiovascular disease.
In our lab, we have noted that macrophages undergoing an Unfolded Protein Response produce synergistic levels of IFN-β, a cytokine that plays diverse roles in many aspects of autoimmune disease, and the pro-inflammatory cytokine IL-23.
Major ongoing projects:
- One form of arthritis, known as spondyloarthritis, is strongly linked to the MHC class I allele HLA-B27, a protein that misfolds. We have found that macrophages from spondyloarthritis patients produce greatly increased IL-23, even apart from obvious UPR induction. Current efforts are focusing on understanding the genetic and biochemical mechanisms supporting cytokine dysregulation in these patients.
- Brucellosis is the most prevalent zoonosis worldwide. Spondyloarthritis is a major complication of this disease. To replicate, the causative organism, Brucella spp. invades macrophages and forms an ER derived vacuole. Brucella also induces a massive reorganization of the ER (imaged by anti-calreticulin staining in the figure) and triggers a UPR. The UPR may affect multiple aspects of pathogenicity, including cytokine production, bacterial replication, host cell apoptosis, antigen presentation and memory. Two current projects are investigating the role of the UPR in Brucella pathogenesis and a separate focus is on the generation of CD8 T cell memory. These projects represent an active collaboration with the Splitter lab on the UW campus.
- A new project has begun in collaboration with Childhood Origins of Asthma (COAST). A recently identified gene polymorphism at 17q21 is one of the most powerful predictors for the development of childhood asthma. One gene at that locus ORMDL3 potentially regulates the UPR. We are determining if subjects with different genotypes have altered UPR induction in response to Rhinovirus and show related consequences for rhinovirus infection.