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Evaluation of T Follicular Helper Cells and Germinal Center Response During Influenza A Virus Infection in Mice
Published on: June 27, 2020
miR-155 promotes T follicular helper cell accumulation during chronic, low-grade inflammation
Ruozhen Hu1, Dominique A Kagele1, Thomas B Huffaker1
1Department of Pathology, Division of Microbiology and Immunology, University of Utah, 4280 JMRB, 15 North Medical Dr. East, Salt Lake City, UT 84112, USA.
Abstract:
Chronic inflammation is a contributing factor to most life-shortening human diseases. However, the molecular and cellular mechanisms that sustain chronic inflammatory responses remain poorly understood, making it difficult to treat this deleterious condition. Using a mouse model of age-dependent inflammation that results from a deficiency in miR-146a, we demonstrate that miR-155 contributed to the progressive inflammatory disease that emerged as Mir146a(-/-) mice grew older. Upon analyzing lymphocytes from inflamed versus healthy middle-aged mice, we found elevated numbers of T follicular helper (Tfh) cells, germinal center (GC) B cells, and autoantibodies, all occurring in a miR-155-dependent manner. Further, Cd4-cre Mir155(fl/fl) mice were generated and demonstrated that miR-155 functions in T cells, in addition to its established role in B cells, to promote humoral immunity in a variety of contexts. Taken together, our study discovers that miR-146a and miR-155 counterregulate Tfh cell development that drives aberrant GC reactions during chronic inflammation.
Insights
MicroRNA-155 drives chronic inflammation by promoting T follicular helper cell development and germinal center reactions. This finding reveals a key mechanism in age-dependent inflammatory diseases and suggests new therapeutic targets.
Area of Science:
- Immunology
- Molecular Biology
- Aging Research
Background:
- Chronic inflammation underlies many life-shortening diseases.
- Mechanisms sustaining chronic inflammation are poorly understood, hindering effective treatment.
- MicroRNAs (miRNAs) play critical roles in immune regulation.
Purpose of the Study:
- To investigate the role of microRNA-155 (miR-155) in age-dependent chronic inflammation.
- To elucidate the cellular and molecular pathways involved in miR-155-driven inflammation.
- To identify potential therapeutic targets for chronic inflammatory conditions.
Main Methods:
- Utilized a mouse model deficient in miR-146a to study age-dependent inflammation.
- Analyzed lymphocyte populations (T follicular helper cells, germinal center B cells) using flow cytometry.
- Generated conditional knockout mice (Cd4-cre Mir155(fl/fl)) to determine the cell-specific function of miR-155.
Main Results:
- miR-155 deficiency ameliorated progressive inflammation in aged miR-146a knockout mice.
- Elevated T follicular helper cells, germinal center B cells, and autoantibodies were observed in inflamed mice, dependent on miR-155.
- miR-155 was found to function in T cells, not just B cells, promoting humoral immunity.
Conclusions:
- miR-146a and miR-155 act antagonistically to regulate T follicular helper cell development.
- Aberrant germinal center reactions driven by Tfh cells contribute to chronic inflammation.
- Targeting the miR-146a/miR-155 axis offers a potential strategy for treating chronic inflammatory diseases.
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