Endoplasmic reticulum resident heat shock protein-gp96 as morphogenetic and immunoregulatory factor in syngeneic pregnancy

Abstract

The severe remodeling of endometrial stroma during blastocyst adhesion and trophoblast invasion initiates at maternal-fetal interface the reaction of evolutionary old heat shock response, in which heat shock proteins, as molecular chaperons, monitor the configurations of newly synthesized proteins and prevent the formation of functionless aggregates of misfolded proteins, targeting them to degradation by a the ubiquitin-proteasome system. In addition, the endoplasmic reticulum (ER)-resident HSPs, such as gp96/GRP94 may, after binding to CD91 and TLRs, elicit antigen-specific and antigen-unspecific immune responses, owing to its peptide-chaperoning capacity and ability to activate APCs. Considering these properties, we examined tissue expression of gp96 at the maternal-fetal interface and in the maternal liver and spleen on the 16th day of undisturbed syngeneic pregnancy and after the treatment with peptidoglycan monomer linked with zinc (PGMZn). The data showed that in undisturbed pregnancy the gp96, CD91 and TLR2 were markedly expressed on extravillous and villous trophoblast. PGM-Zn enhanced these findings, as well as the number of uterine natural killer cells and local NFκB immunoreactivity. Gp96 expression arose also in the maternal spleen and liver, where an accumulation of NKT cells or γδT lymphocytes was seen. The data point to roles of gp96 in maintenance of proteostasis and local and systemic immune balance in pregnancy complicated by infection.