NIH VideoCast - Quantitative Control of Macrophage Inflammatory Responses

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Quantitative Control of Macrophage Inflammatory Responses

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Air date:	Wednesday, April 20, 2016, 4:15:00 PM Time displayed is Eastern Time, Washington DC Local
Views:	Total views: 376 (57 Live, 319 On-demand)
Category:	Immunology
Runtime:	00:50:39
Closed captioning:	Check box to display CC outside of the video Note: You can drag the captioning window around and resize it
Description:	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 system operating in both mouse and human macrophages, in which NF-kB dependent ‘danger discrimination’ is facilitated by strict control of MAPK activity. Genome wide association studies have linked MAPK-regulating phosphatases with chronic inflammatory diseases of the respiratory and gastrointestinal tracts, suggesting that altered MAPK control may contribute to aberrant inflammation at barrier sites. We have utilized computational modeling to uncover novel phosphatase-mediated MAPK feedback mechanisms and are currently using this approach to investigate how modest changes in the expression or activity of key regulators, resulting from genetic variation or pharmacological manipulation, can impact macrophage sensitivity to microbial products.

NLM Title:	Quantitative control of macrophage inflammatory responses / Rachel A. Gottschalk ; Immunology Interest Group.
Author:	Gottschalk, Rachel A. National Institutes of Health (U.S.). Immunology Interest Group,
Publisher:
Abstract:	(CIT): 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-[kappa]B 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 system operating in both mouse and human macrophages, in which NF-kB dependent "danger discrimination" is facilitated by strict control of MAPK activity. Genome wide association studies have linked MAPK-regulating phosphatases with chronic inflammatory diseases of the respiratory and gastrointestinal tracts, suggesting that altered MAPK control may contribute to aberrant inflammation at barrier sites. We have utilized computational modeling to uncover novel phosphatase-mediated MAPK feedback mechanisms and are currently using this approach to investigate how modest changes in the expression or activity of key regulators, resulting from genetic variation or pharmacological manipulation, can impact macrophage sensitivity to microbial products.
Subjects:	Immunity, Innate Inflammation Mediators Macrophages--immunology Signal Transduction Toll-Like Receptors--metabolism
Publication Types:	Lecture Webcast

NLM Classification:	QW 541
NLM ID:	101682342
CIT Live ID:	18928
Permanent link:	https://videocast.nih.gov/watch=18928

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