ROLE OF CXCL12 AND CXCR4 IN A MOUSE MODEL OF SS
Kurosawa, Mie Tokushima University
Arakaki, Rieko Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Tsunematsu, Takaaki Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Kudo, Yasusei Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Sprent, Jonathan Garvan Institute of Medical Research
Thesis or Dissertation
Objective. Dysregulated chemokine signaling contributes to autoimmune diseases by facilitating aberrant T-cell infiltration into target tissues, but the specific cytokines, receptors, and T-cell populations remain largely unidentified. Role of the potent chemokine CXCL12 and its receptor CXCR4 in T-cell autoimmune response was examined using alymphoplasia (aly)/aly mice, a Sjögren’s syndrome (SS) model.
Methods. T-cell phenotypes in the salivary gland of aly/aly mice were evaluated using immunological analysis. In vitro migration assay was used to assess T-cell migratory activity toward several chemokines. Gene expression of chemokine receptors, and transforming growth factor (TGF)β receptors was measured with quantitative reverse transcription-polymerase chain reaction. The CXCR4 antagonist AMD3100 was administered to the aly/aly mice to evaluate its suppressive effect on autoimmune lesions.
Results. Effector memory T (TEM) cells derived from aly/aly mice demonstrated higher in vitro migratory activity toward CXCL12 than aly/+ TEM cells. CXCL12 expression was specifically upregulated in the SS target cells of aly/aly mice. TEM cells from RelB−/− mice, but not nuclear factor (NF)-κB1−/− mice, also showed high migratory activity toward CXCL12, implicating a nonclassical NF-κB2/RelB pathway in the regulation of TEM cell migration. TEM cells from aly/aly mice also overexpressed TGFβ receptors I and II. The CXCR4 antagonist AMD3100 suppressed autoimmune lesions in aly/aly mice by reducing TEM cell infiltration.
Conclusion. Our results suggest that the NF-κB2/RelB pathway regulates T-cell migration to autoimmune targets through TGFβ/TGFβR-dependent regulation of CXCL12−CXCR4 signaling. This suggests that these signaling pathways are potential therapeutic targets for treating autoimmune diseases.
Arthritis & Rheumatology
American College of Rheumatology|Wiley
This is the peer reviewed version of the following article: Kurosawa, M. , Arakaki, R. , Yamada, A. , Tsunematsu, T. , Kudo, Y. , Sprent, J. and Ishimaru, N. (2017), NF‐κB2 Controls the Migratory Activity of Memory T Cells by Regulating Expression of CXCR4 in a Mouse Model of Sjögren's Syndrome. Arthritis Rheumatol, 69: 2193-2202, which has been published in final form at https://doi.org/10.1002/art.40230. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
|DOI (Published Version)|
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k3174_abstract.pdf 115 KB
k3174_review.pdf 365 KB
k3174_fulltext.pdf 8.72 MB
|MEXT report number||
Doctor of Dental Science