GPR54 deficiency reduces the Treg population and aggravates experimental autoimmune encephalomyelitis in mice

Abstract

GPR54 is highly expressed in the central nervous system and plays a crucial role in pubertal development. However, GRP54 is also expressed in the immune system, implying possible immunoregulatory functions. Here we investigated the role of GPR54 in T cell and immune tolerance. GPR54 deficiency led to an enlarged thymus, an increased number of thymocytes, and altered thymic micro-architecture starting around puberty, indicating GPR54 function in T-cell development through its regulatory effect on the gonadal system. However, flow cytometry revealed a significant reduction in the peripheral regulatory T cell population and a moderate decrease in CD4 single-positive thymocytes in prepubertal Gpr54 mice. These phenotypes were confirmed in chimeric mice with GPR54 deficient bone marrow-derived cells. In addition, we found elevated T cell activation in peripheral and thymic T cells in Gpr54 mice. When intact mice were immunized with myelin oligodendrocyte glycoprotein, a more severe experimental autoimmune encephalomyelitis (EAE) developed in the Gpr54 mice. Interestingly, aggravated EAE disease was also manifested in castrated and bone marrow chimeric Gpr54 mice compared to the respective wild-type control, suggesting a defect in self-tolerance resulting from GPR54 deletion through a mechanism that bypassed sex hormones. These findings demonstrate a novel role for GPR54 in regulating self-tolerant immunity in a sex hormone independent manner.

Kisspeptin prevents pregnancy loss by modulating the immune microenvironment at the maternal‐fetal interface in recurrent spontaneous abortion

“…As kisspeptin regulated Treg cells in the spleen and uterus of mice, its specific mechanism was investigated. A study has previously confirmed the expression of GPR54 in CD4 + T cells of mouse thymus and spleen 16 . Therefore, whether GPR54 could be expressed on Treg cells, allowing them to bind to kisspeptin and exert its effects, was explored.…”

“…Kisspeptin/GPR54 has been observed to inhibit the function of CD8 + T cells and promote lung cancer progression 15 . Furthermore, GPR54 −/− mice have been found to exhibit a reduced proportion of CD4 + FOXP3 + Treg cells and develop a more severe form of experimental autoimmune encephalomyelitis 16 . Hence, kisspeptin is crucial for immune modulation, but its specific mechanism in the pathogenesis of RSA remains unclear.…”

Kisspeptin Suppresses Inflammasome-NLRP3 Activation and Pyroptosis Caused by Hypothyroidism at the Maternal-Fetal Interface of Rats

“…Pharmacological inhibitors of the inflammasome pathway have broad therapeutic potential for the treatment of diseases that involve activation of this process [ 21 , 22 , 27 , 29 ]. Moreover, previous studies have demonstrated the immunomodulatory activity of kisspeptin on monocytes, neutrophils, and regulatory T lymphocytes [ 34 , 35 , 36 ]. However, there is no information on whether kisspeptin is also capable of modulating the activation of the inflammasome-NLRP3 pathway and pyroptosis.…”