My laboratory is interested in how cytokines and inflammatory factors regulate the activation and function of innate immune and stromal cells, with a focus on macrophages and synovial fibroblasts. Cytokines are key regulators of immune responses that have been implicated in the pathogenesis of inflammatory and autoimmune diseases. We study cytokine signaling, mechanisms of cytokine production, and epigenetic regulation of inflammatory gene expression to discover new mechanisms and therapeutic targets for inflammatory and autoimmune diseases such as rheumatoid arthritis and lupus.
We have worked extensively on signal transduction crosstalk between cytokines that activate the Jak-STAT signaling pathway, such as IFN-gamma, IFN-alpha and IL-10, and inflammatory activators of macrophages such as Toll-like receptor ligands and TNF. We have connected these signaling pathways with downstream chromatin-mediated and epigenetic mechanisms that regulate gene expression and inflammatory cell phenotypes. This work uses primary human cells relevant for disease pathogenesis, disease models, and includes genome-wide approaches to study gene expression, epigenomic mechanisms, and identification and characterization of enhancers.
We are currently studying how cytokines such as IFNs and TNF reprogram macrophage responses to the environment by altering transcription factor networks, chromatin states, cell metabolism, and the epigenomic landscape of enhancers. Such reprogramming results in macrophages that are hyper-responsive (‘primed’) or desensitized (‘tolerized’) to inflammatory challenges. Understanding of underlying mechanisms will enable novel therapeutic approaches to selectively modulate expression of key inflammatory genes such as TNF and IL6 to suppress inflammatory diseases. Additional areas of interest include mechanisms that sustain inflammatory responses in synovial fibroblasts, functional coupling between macrophages and fibroblasts, transcription factor networks that control osteoclast differentiation and pathologic bone resorption, and using a transgenic approach that couples bacterial artificial chromosomes (BACs) and CRISPR-Cas9 genome editing to study the regulation of human autoimmunity-associated genes such as A20/TNFAIP3.
The laboratory integrates basic science investigation of signaling and epigenetic mechanisms with translational research using disease models and analysis of human disease samples with genome wide approaches such as RNA-seq, ChIp-seq, and ATAC-seq. We are incorporating a precision medicine approach to identify disease mechanisms and the best therapies for individual patients. Our long term goals are to identify signaling and epigenetic mechanisms that can be targeted by new therapies for inflammatory and autoimmune diseases.