Trem2 prevents adverse pregnancy outcomes induced by Toxoplasma gondii by promoting PPARγ-mediated P-STAT6 signaling

Decidual macrophages (DMs), required for the maintenance of a successful pregnancy, are vital target cells for Toxoplasma gondii (T. gondii) during adverse pregnancy induced by T. gondii. Trem2 is a functional immune receptor on the surface of DMs, governing cell survival and phagocytosis. Our previous study demonstrated that Trem2 deficiency aggravates T. gondii-induced adverse pregnancy outcomes. However, Trem2-related downstream signaling pathways in T. gondii-induced adverse pregnancy outcomes remains unclear. Here, we demonstrated a significant decrease in PPARγ and phosphorylated-STAT6 (P-STAT6) in mouse placentas following T. gondii infection. By using a Trem2 knockout mouse model, we found that Trem2 deficiency failed to affect the expressions of P-STAT6 and PPARγ in infected mouse placentas, peritoneal macrophages and bone marrow-derived macrophages (BMDMs). Consistently, overexpression of Trem2 in macrophages significantly activated the downstream signaling pathway and partially reversed the inhibitory effects of T. gondii antigens on P-STAT6 and PPARγ, similar to the effect of PPARγ agonists. Altogether, our study identified Trem2 as a key regulator of PPARγ-mediated P-STAT6 signaling pathways in adverse pregnancy outcomes due to T. gondii infection. Our novel findings concerning Trem2 and its downstream PPARγ-mediated P-STAT6 signaling pathways might provide new preventive and therapeutic targets for toxoplasmosis.

蜕膜巨噬细胞（decidual macrophages, DMs）是维持妊娠顺利进行的必需细胞，同时也是刚地弓形虫（Toxoplasma gondii, T. gondii）诱导不良妊娠过程中的关键靶细胞。Trem2是蜕膜巨噬细胞表面的功能性免疫受体，可调控细胞存活与吞噬功能。本团队前期研究证实，Trem2基因缺失会加重刚地弓形虫诱导的不良妊娠结局。然而，在刚地弓形虫诱导的不良妊娠过程中，与Trem2相关的下游信号通路仍未阐明。本研究发现，刚地弓形虫感染后小鼠胎盘中的过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor γ, PPARγ）与磷酸化STAT6（phosphorylated-STAT6, P-STAT6）水平显著下调。通过构建Trem2基因敲除小鼠模型，本研究发现，在感染小鼠的胎盘、腹腔巨噬细胞与骨髓源巨噬细胞（bone marrow-derived macrophages, BMDMs）中，Trem2缺失并不会影响P-STAT6与PPARγ的表达水平。与之相符的是，在巨噬细胞中过表达Trem2可显著激活下游信号通路，并部分逆转刚地弓形虫抗原对P-STAT6与PPARγ的抑制作用，该效果与PPARγ激动剂的作用类似。综上，本研究证实Trem2是刚地弓形虫感染所致不良妊娠结局中PPARγ介导的P-STAT6信号通路的关键调控因子。本研究关于Trem2及其下游PPARγ介导的P-STAT6信号通路的全新发现，可为弓形虫病的预防与治疗提供全新的潜在靶点。