Macrophages have been implicated in the pathogenesis of several autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel disease. The long term goals of this project are to understand how inflammatory macrophage activation (and de-activation) is regulated, with the associated goal of using this knowledge to develop new therapies that selectively suppress pathogenic macrophage functions, while preserving homeostatic functions and host defense. Two molecules critically important for de-activation of macrophages are A20 (encoded by TNFAIP3) and IL-10, which suppress, respectively, inflammatory signaling and gene transcription, and thus can cooperate to restrain inflammatory macrophage activation. They can contribute to a feedback-inhibited state termed macrophage tolerance, which is characterized by attenuated signaling and specific silencing of inflammatory cytokine genes. Understanding mechanisms underlying gene-specific regulation in tolerized macrophages is important for developing approaches to selectively modulate macrophage functions. Allelic variants (single nucleotide polymorphisms (SNPs)) at the TNFAIP3 and IL10 loci are tightly linked with various autoimmune diseases, including SLE and RA. Autoimmunity-associated SNPs at TNFAIP3 and IL10 loci mostly fall outside of coding regions and likely confer disease susceptibility by affectig the function of DNA regulatory elements (enhancers) and thus the expression, rather than the function, of A20 or IL-10. The key role of enhancers in regulating gene expression and the emerging linkage of enhancers with diseases highlight the importance of understanding enhancer function. Greater understanding of how genes and enhancers are regulated opens opportunities to devise new therapeutic approaches to target pathways that regulate gene expression, rather than targeting gene products. Based on our overarching hypothesis that augmentation of inhibitory pathways and mechanisms represents an effective approach to therapy of autoimmune/inflammatory diseases, we investigated mechanisms that regulate IL10 and TNFAIP3 expression and macrophage tolerance. We identified chromatin-mediated epigenetic mechanisms that regulate IL10 and TNFAIP3 expression and identified key enhancers at these gene loci. We found that tolerance of human macrophages is mediated in part by mechanisms that alter chromatin states and regulate enhancer function and can explain gene-specific regulation. In this project, we will investigate mechanisms that control enhancer function to regulate IL-10 and A20 expression and tolerance induction, and the functional consequences of disruption of these pathways in vitro and in vivo in autoimmune disease models. We anticipate our studies will yield insights that can be used to develop therapies that selectively augment inhibitory pathways to suppress pathogenic macrophage functions in autoimmune and inflammatory diseases.

Public Health Relevance

Macrophages have been implicated in several autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel disease. The long term goals of this project are to understand how inflammatory macrophage activation (and de-activation) are regulated, and to use this knowledge to develop new therapies. This project will focus on understanding the regulation macrophage genes and pathways that play a key role in suppressing inflammatory responses to gain knowledge that can be used to turn off macrophages to effectively and safely treat autoimmune and inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046712-17
Application #
9001236
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Peyman, John A
Project Start
2000-03-01
Project End
2020-02-29
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
17
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Hospital for Special Surgery
Department
Type
DUNS #
622146454
City
New York
State
NY
Country
United States
Zip Code
10021
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