Thymic alterations induced by partial hepatectomy: upregulation of glycoprotein 96,
CD91 and TLR2 and generation of regulatory T cells
Hrvoje Jakovac, Mira Ćuk, Zlatko Trobonjača, Ines Mrakovčić-Šutić and Biserka Radošević-Stašić
Department of Physiology and Immunology, Medical Faculty, University of Rijeka, Rijeka, Croatia
Offprint requests to: Biserka Radosevic-Stasic, Medical Faculty, University of Rijeka, B. Branchetta 22, 51000 Rijeka, Croatia. e-mail: firstname.lastname@example.org
Summary. Glycoprotein 96 (gp96) is an endoplasmic reticulum (ER)-resident heat shock protein. It controls the folding of nascent membrane-spanning and secretory proteins, participates in stress-induced unfolded protein response (UPR) and in pathways leading to proteolysis of damaged proteins through ER-associated degradation pathways and chaperone-mediated autophagy. In addition, gp96 controls the steroid biosynthesis and Ca2+ homeostasis and participates in insulin-IGF/signaling pathways. Besides, owing to its peptide chaperone capacity and ability to interact with antigen-presenting cells, gp96 has been implicated in priming of innate and adaptive immunity.
In an attempt to visualize the intensity of ER-stress in thymus and possible participation of gp96 in generation of auto-reactive T cell clones that were detected in regenerating liver, in this study we investigated the dynamics of gp96 expression in partially hepatectomized (pHx) and sham Hx mice. Simultaneously, we detected the thymic expression of receptors responsible for endocytosis of gp96-chaperoned peptides (CD91) and intracellular activation of ER-stress pathways (TLR2), as well as the expression of TGF-β and the distribution of CD4+CD25+FoxP3+ cells. The data have shown that both pHx and sham Hx induced an accelerated apoptosis and hypoplasia in thymus. Partial Hx induced, however, a higher expression of gp96, the translocation of the CD91, TLR2 and TGF-β immunostaining from medulla to cortex and an appearance of Treg cells.
The data show that pHx triggers in thymus the ER-stress and UPR response and suggest that gp96 participates in the generation of natural Treg cells, which might be involved in the control of liver regeneration in the periphery. Histol Histopathol 30, 931-943 (2015)
Key words: Liver regeneration, Thymus, Glycoprotein 96, CD91, TLR2, TGF-beta, Regulatory T cells