Understanding Pattern Recognition Receptor Signaling and its Effect on Hematopoietic Stem Cells.

Genome-wide SiRNA Screen to Identify Regulators of NOD2;Model of Bacterial Infection to Assess HSC Function and Localization;Implications for Crohn"s Disease and Extramedullary Hematopoiesis;Pathology;Health Sciences;Science;Molecular & Cellular Pathology

Burberry, Aaron PhillipFerguson, David O. ;

University of Michigan

关键词: Genome-wide SiRNA Screen to Identify Regulators of NOD2;    Model of Bacterial Infection to Assess HSC Function and Localization;    Implications for Crohn";    s Disease and Extramedullary Hematopoiesis;    Pathology;    Health Sciences;    Science;    Molecular & Cellular Pathology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/102495/aaronbur_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Pattern recognition receptors (PRRs) sense unique and conserved structures common to many types of microorganisms and activate pro-inflammatory signaling cascades that are important for mounting effective immune responses, but aberrant regulation of PRR signaling can lead to autoimmunity.Polymorphisms in NOD2, an intracellular PRR, are associated with increased risk of developing the inflammatory bowel disorder Crohn’s disease.To gain insight into how NOD2 signaling is regulated, we performed a genome-wide siRNA screen in which NOD2-induced NF-κB activation was assessed using a luciferase reporter system.Using this strategy, we identified and validated hundreds of novel regulators of the NOD2 and NF-κB signaling pathway, some of which were previously implicated in Crohn’s disease susceptibility.By comparing our results with publicly available protein-protein interaction databases, we were able to visualize networks of genes, including the linear ubiquitin chain assembly complex, that are important for mediating NOD2-dependent responses.Classically, PRRs are thought to function in differentiated cells to orchestrate inflammation, but recent evidence suggests that hematopoietic stem cells (HSCs), which maintain production of all blood cells throughout life, express PRRs and could be important for supporting immune responses during infection though the mechanisms underlying this function are unclear.We found that systemic infection of mice with the gram negative bacterium Escherichia coli resulted in moderate reduction of HSC activity in bone marrow and vastly expanded HSC activity in spleen, indicative of extramedullary hematopoiesis.Expansion of splenic HSCs was reduced in mice deficient for the PRR TLR4 or the adaptor protein RIPK2, which is required for NOD1 and NOD2 signaling, implicating PRRs in the regulation of HSCs during infection.PRR signaling in radio-resistant cells was important for promoting progenitor expansion in spleen, suggesting an indirect mechanism.We found that expansion of splenic HSCs was dependent on dual activation of NOD1 and TLR4 and production of granulocyte-colony stimulating factor.Altogether, these results provide a global view of the mechanisms that regulate PRR signaling and provide insight into the pathways that facilitate extramedullary hematopoiesis in the context of infection.