Department of Immunology, Peking University School of Basic Medical Sciences, Beijing, China.
NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China.
Clin Exp Immunol. 2021 Jan;203(1):125-136. doi: 10.1111/cei.13528. Epub 2020 Oct 23.
Pattern recognition receptors, such as Toll-like receptors (TLRs), play an important role in the host defense against invading microbial pathogens. Their activation must be precisely regulated, as inappropriate activation or overactivation of TLR signaling pathways may result in inflammatory disorders, such as septic shock or autoimmune diseases. TMEM106A is a type II transmembrane protein constitutively expressed in macrophages. Our current study demonstrated that TMEM106A levels were increased in macrophages upon lipopolysaccharide (LPS) stimulation, as well as in the peripheral monocytes of patients with sepsis. Tmem106a knockout mice were more sensitive to lipopolysaccharide (LPS)-induced septic shock than wild-type mice. Further experiments indicated that Tmem106a ablation enhanced the expression of CD80, CD86 and major histocompatibility complex (MHC)-II in mouse macrophages upon LPS stimulation, accompanied with up-regulation of tumor necrosis factor (TNF)-α, interleukin (IL)-6, interferon (IFN)-β and inducible nitric oxide synthase (iNOS), indicating the activation of macrophages and polarization towards the M1 inflammatory phenotype. Moreover, elevated mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling were found to be involved in the LPS-induced inflammatory response in Tmem106a macrophages. However, this effect was largely abrogated by macrophage deletion in Tmem106a mice. Therefore, deficiency of Tmem106a in macrophages may enhance the M1 polarization in mice, resulting in inflammation. This suggests that TMEM106A plays an important regulatory role in maintaining macrophage homeostasis.
模式识别受体，如 Toll 样受体（TLRs），在宿主防御入侵的微生物病原体中起着重要作用。它们的激活必须得到精确的调节，因为 TLR 信号通路的不适当激活或过度激活可能导致炎症性疾病，如败血症休克或自身免疫性疾病。TMEM106A 是一种在巨噬细胞中持续表达的 II 型跨膜蛋白。我们目前的研究表明，TMEM106A 水平在巨噬细胞受到脂多糖（LPS）刺激时以及败血症患者的外周单核细胞中增加。Tmem106a 敲除小鼠对脂多糖（LPS）诱导的败血症休克比野生型小鼠更敏感。进一步的实验表明，Tmem106a 缺失增强了 LPS 刺激下小鼠巨噬细胞中 CD80、CD86 和主要组织相容性复合体（MHC）-II 的表达，伴随着肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6、干扰素（IFN）-β 和诱导型一氧化氮合酶（iNOS）的上调，表明巨噬细胞的激活和向 M1 炎症表型的极化。此外，发现丝裂原激活的蛋白激酶（MAPK）和核因子 kappa B（NF-κB）信号通路参与了 Tmem106a 巨噬细胞中 LPS 诱导的炎症反应。然而，这种效应在 Tmem106a 小鼠的巨噬细胞缺失中被大大削弱。因此，巨噬细胞中 Tmem106a 的缺失可能增强了小鼠的 M1 极化，导致炎症。这表明 TMEM106A 在维持巨噬细胞稳态中起着重要的调节作用。
