Quantitative Control of Macrophage Inflammatory Responses

Immunology Interest Group Rachel Gottschalk obtained her bachelor’s degree in Biology from Emory University in 2005 and went on to earn her Immunology Ph.D. from Weill Cornell Graduate School of Medical Sciences. She carried out her thesis work in the laboratory of James Allison at Memorial Sloan Kettering Cancer Center, studying distinct influences of peptide-MHC quality and quantity on T cells responses, including induction of regulatory T cells. Rachel joined the Laboratory of Systems Biology, NIAID in 2012 as a post-doctoral fellow, where she currently studies macrophage signal integration under the mentorship of Ronald Germain. Rachel’s efforts are aimed at elucidating quantitative control of inflammatory thresholds. Abstract: The innate immune system generates context-specific responses to microbial products, distinguishing low-level homeostatic stimuli from those of invasive pathogens, but we lack a mechanistic understanding of the signaling logic that underlies such operational discrimination. Using quantitative approaches, we found multiple thresholds for activating distinct signaling pathways that dictated stimulus strength-dependent responses of TLR4-stimulated macrophages. Inflammatory mediator production had a threshold controlled by switch-like MAPK activation, whereas NF-κB activity and restricted gene expression occurred at ligand concentrations below this threshold. Our results thus reveal a tightly regulated low-noise, robust innate immune response sy...
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