Innate Immunity: Influence of the Extracellular Matrix Component Versican in Response to Lung Infections
Final Report Abstract
Lung infections place a higher burden on public health than other major diseases such as HIV/AIDS, cancer, coronary heart disease, and strokes. And still little is known about the role of the innate immune system, which is the body’s first line of defense against lung infection and its interaction with the extracellular matrix (ECM). Only recently has it been recognized that components of the ECM participate in and partially control events that drive the inflammatory response in many different diseases. Evidence is mounting to indicate that the ECM molecule versican is a central player in inflammation in a number of diseases. Our central hypothesis was that specialized ECMs containing versican are formed during viral- or allergen-induced lung inflammation. We further hypothesized, that this matrix specifically interacts with and provides temporal and spatial cues for leukocytes as they enter the lung impacting their phenotype and providing fine-tuned control of the inflammatory response. Supporting our hypothesis, we have discovered that versican accumulates in the lung tissue, when lungs are exposed to allergens such as cockroach antigen (CRA), bacteria such as E. coli, Pseudomonas aeruginosa, viruses such as respiratory syncytial virus (RSV) and influenza. Furthermore, our studies indicate that the synthesis and accumulation of versican is highly regulated and produced by at least two different lung cell populations, interstitial fibroblasts and macrophages when the cells are exposed to these inflammatory agonists. We now hypothesize that interfering with this versican-enriched ECM will dampen the inflammatory response and delay lung fibrosis. The development of mouse models in which the versican gene has been selectively deleted will be crucial to test whether versican plays a causative or responsive role in the development of lung inflammation. Understanding the mechanisms that regulate versican transcription in lungs will likely provide targets for novel therapeutic interventions in lung diseases.
Publications
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Type 1 Diabetes: Involvement of Extracellular Matrix in Immune-Mediated Pancreatic Islet Destruction. Abstract book, American Society for Biochemistry and Molecular Biology (ASBMB) meeting 11-2012 San Diego
Nagy N, Kaber G, Campbell DJ, Wight TN
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Expression and translation of the COX- 1b gene in human cells--no evidence of generation of COX-1b protein. Biol Chem. 2013 Jun;394(6):753-60
Reinauer C, Censarek P, Kaber G, Weber AA, Steger G, Klamp T, Schrör K
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Involvement of Hyaluronan and Related Extracellular Matrix Molecules in Immune-Mediated Pancreatic Islet Destruction. Abstract book, Keystone meeting 04-2013 Whistler
Nagy N, Kaber G, Campbell DJ, Bollyky PL, Wight TN
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Type 1 Diabetes: Involvement of Hyaluronan and Related Extracellular Matrix Molecules in Immune-Mediated Pancreatic Islet Destruction. Abstract book, International Society for Hyaluronan Sciences (ISHAS) meeting 06-2013 Oklahoma City
Nagy N, Kaber G, Campbell DJ, Day AJ, Bollyky PL, Wight TN
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Hyaluronan is Crucial for Autoimmune Diabetes Development and Progression. Abstract book, American Society for Matric Biology (ASMB) meeting 10-2014 Cleveland
Nagy N, Kaber G, Johnson PY, Campbell DJ, Gebe JA, Day AJ, Wight TN, Bollyky PL
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Phosphorylation of sterol regulatory element-binding protein (SREBP)-1c by p38 kinases, ERK and JNK influences lipid metabolism and the secretome of human liver cell line HepG2. Arch Physiol Biochem. 2014 Dec;120(5):216-27
Knebel B, Lehr S, Hartwig S, Haas J, Kaber G, Dicken HD, Susanto F, Bohne L, Jacob S, Nitzgen U, Passlack W, Muller-Wieland D, Kotzka J
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Inhibition of Hyaluronan Synthesis Restores Immune Tolerance During Autoimmune Insulitis. Journal of Clinical Investigation, 2015;125(10):3928–3940
Nagy N, Kaber G, Johnson PY, Gebe JA, Preisinger A, Falk B, Sunkari VG, Gooden MD, Vernon RB, Bogdani M, Kuipers HF, Day AJ, Campbell DJ, Wight TN, Bollyky PL
