MicroRNA (miRNA), have been demonstrated recently to be pivotal in regulating immune responses. Among them, miR-155 is one of the most prominent miRNAs in the immune system. Genetic loss-of-function studies have demonstrated that miR-155 controls multiple aspects of the immune responses through silencing a wide range of targets in various immune cell populations. Our previous work suggested that Foxp3 drives high expression of miR-155 and, thereby promotes the competitive fitness of Treg cells by inducing SOCS1 down-regulation. Subsequent studies conducted by other groups have implied a role for the miR-155/SOCS1 axis in tuning macrophage responsiveness to LPS-induced endotoxin tolerance as well as cytokine production by dendritic cells. However, since miRNAs mediate their effects through targeting a broad range of mRNA species, diverse immune response related phenotypes in miR-155 deficient mice can be attributed to changes in miR-155 target genes other than SOCS1. Here, we propose a multifaceted study employing genetic, biochemical, immunological approaches and whole animal experimentation to comprehensively examine the role for miR-155-mediated SOCS1 regulation. First, we will examine the combined effects of SOCS1 deficiency/haploinsufficiency and miR-155 deficiency to see if aspects of the observed miR-155 phenotype are reversed by loss of SOCS1 function. Next, by generating a new mouse model with mutations specifically disrupting the interaction between miR-155 and SOCS1 gene (SOCS1KI/KI mice) and by comparing these mice to miR-155-deficient mice, we will be able to isolate the effects of miR-155 on a single target and to explore the biological significance of SOCS1 repression in miR-155-mediated immune regulation. Moreover, as miR-155 has been strongly implicated in promoting inflammatory responses required for the development of autoimmunity, in the second specific aim, we will elucidate the role of SOCS1 repression by miR-155 in EAE, a well-established animal model of multiple sclerosis. The availability of SOCS1KI/KI mice affords the opportunity to examine the contribution of miR-155-mediated SOCS1 repression to the control of autoimmune disease. Moreover, using T cell transfer experiments as well as mixed BM chimeras studies, more refined insights into the respective role of miR-155-mediated SOCS1 repression within different hematopoietic lineages will be determined. Finally, we will investigate effector mechanisms underlying miR-155-mediated SOCS1 repression in promoting EAE disease phenotype. The proposed studies will greatly extend our fundamental knowledge of SOCS1 repression in miR-155-mediated immune regulation and provide further insights into this specific miRNA-target partnership in regulating human health and disease.

Public Health Relevance

The proposed studies aim to facilitate basic understanding of the effects of miRNA on a single target and to explore the biological significance of such regulation in the context of autoimmunity. The results obtained from these studies will provide critical insights into manipulating miRNA-dependent post-transcriptional regulation as a novel therapeutic approach for not only autoimmunity but also many other immunological human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI103646-01
Application #
8427854
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Esch, Thomas R
Project Start
2013-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$193,750
Indirect Cost
$68,750
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Lee, Hyang-Mi; Nguyen, Duc T; Lu, Li-Fan (2014) Progress and challenge of microRNA research in immunity. Front Genet 5:178