Oncotarget

Research Papers: Immunology:

The TRPV1 ion channel regulates thymocyte differentiation by modulating autophagy and proteasome activity

Consuelo Amantini _, Valerio Farfariello, Claudio Cardinali, Maria Beatrice Morelli, Oliviero Marinelli, Massimo Nabissi, Matteo Santoni, Laura Bonfili, Valentina Cecarini, Anna Maria Eleuteri and Giorgio Santoni

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Oncotarget. 2017; 8:90766-90780. https://doi.org/10.18632/oncotarget.21798

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Abstract

Consuelo Amantini1,*, Valerio Farfariello2,*, Claudio Cardinali3,4, Maria Beatrice Morelli3,4, Oliviero Marinelli1, Massimo Nabissi3, Matteo Santoni3, Laura Bonfili1, Valentina Cecarini1, Anna Maria Eleuteri1 and Giorgio Santoni3

1 School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy

2 University of Lille, INSERM U1003 - PHYCEL - Physiologie Cellulaire, Lille, France

3 School of Pharmacy, Experimental Medicine Section, University of Camerino, Camerino, Italy

4 Department of Molecular Medicine, Sapienza University, Rome, Italy

* These authors have contributed equally to this work

Correspondence to:

Consuelo Amantini, email:

Keywords: ER stress, capsaicin, TRPV1, TRPV1 KO mice, autophagy, Immunology and Microbiology Section, Immune response, Immunity

Received: July 28, 2017 Accepted: September 20, 2017 Published: October 11, 2017

Abstract

Autophagy and the ubiquitin-proteasome system (UPS) control thymus cell homeostasis under resting and endoplasmic reticulum (ER) stress conditions. Several evidence support a cross-talk between UPS and autophagy; abrogation of UPS responses stimulates autophagy, and vice versa the inhibition of autophagy alters the UPS functions.

Herein, we found that TRPV1 activation induces ER stress, proteasome dysfunction and autophagy in thymocytes by modulating the expression of UPR-related genes. The TRPV1-mediated autophagy prevents the UPR activation by inhibiting BiP, Grp94 and ERp57 chaperone protein expression.

Thymocytes from TRPV1 KO mice display both autophagy and proteasome dysfunctions, resulting in increased apoptotic cells and reduced total DP thymocyte number.

In addition, positive selection of thymocytes triggered by anti-TCRβ/CD2 Ab-mediated costimulation induces apoptosis in thymocytes from TRPV1 KO as compared with WT mice. Stimulation of TRPV1 KO thymocytes with anti-TCRβ/CD2 mAbs modulates the expression of CD4 antigen on purified DP thymocytes, with reduced number of mature, single positive (SP) CD4 and increased number of immature SP CD4low and DP CD4lowCD8+ thymocytes, further supporting the intrinsic role of TRPV1 in T cell maturation. Finally, a reduction in CD8+ and CD4+ T cells is evidenced in the peripheral blood and spleen of TRPV1 KO, as compared with WT mice. Therapeutic strategy by restraining or stimulating the TRPV1 expression and functions in thymocytes might represent a new pharmacological tool in the regulation of different inflammatory T cell responses.


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