調節型核醣核酸內切酶 REGNASE-1 對 M2a 巨噬細胞功能的影響及其與腫瘤生長的關聯性

Abstract

免疫網絡是一個複雜的系統，需要先天性免疫系統和適應性免疫系統之間的緊密配合，以在促發炎和抗發炎微環境中實現有效的反應。巨噬細胞透過啟動不同的極化狀態在先天免疫系統中發揮關鍵作用。它們大致分為 M1（促發炎）和 M2（抗發炎）巨噬細胞。在 M2 巨噬細胞中，M2a 亞型是研究最充分的亞型之一，並且透過 細胞介白素 4 (IL-4) 和/或 細胞介白素 13 (IL-13) 刺激而極化。調節型核糖核酸內切酶REGNASE-1 具有核糖核酸酶和去泛素酶活性，已知在促發炎狀態下參與各種免疫細胞的免疫抑製作用。然而，其在 M2 巨噬細胞中的調節功能仍不清楚。於本論文中，我們透過分析 mRNA定序數據中的差異表達基因來研究 REGNASE-1 在 M2a 巨噬細胞中的作用，並觀察到兩種 T 細胞趨化因子 CCL17 和 CCL22 的顯著減少。隨後的表徵表明，REGNASE-1 透過降解針對這些基因的 microRNA 來增強這些 mRNA 的穩定性。此外，在確認REGNASE-1 吸引調節性T 細胞 的能力後，我們觀察到，當將Lewis 肺癌細胞植入巨噬細胞特異性Regnase-1 敲除小鼠中時，腫瘤重量顯著減少。總的來說，我們的研究結果闡明了 REGNASE-1 在 M2a 中的作用及其對腫瘤生長的潛在影響。

The immune network is a complex system requiring cohesive cross-talk between the innate and adaptive immune systems to achieve efficient responses in both pro-inflammatory and anti-inflammatory microenvironments. Macrophages play a key role in the innate immune system, initiating distinct polarization states. They are broadly classified into M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages. Among the M2 macrophages, the M2a subtype is one of the most well-studied and is polarized through IL-4 and/or IL-13 stimulation. REGNASE-1, which possesses both ribonuclease and deubiquitinase activities, is known to participate in immunosuppressive roles across various immune cells during pro-inflammatory states. However, its regulatory function in M2 macrophages remains unclear. Here, we investigate the role of REGNASE-1 in M2a macrophages by analyzing differentially expressed genes in mRNA sequencing data and observe significant reductions in two T cell-attractant chemokines, CCL17 and CCL22. Subsequent characterization reveals that REGNASE-1 enhances the stability of these mRNAs by degrading microRNAs targeting these genes. Furthermore, upon confirming the ability of REGNASE-1 to attract regulatory T cells (Tregs), we observed a marked reduction in tumor weight when Lewis lung carcinoma cells are implanted in macrophage-specific Regnase-1 knockout mice. Collectively, our findings elucidate the role of REGNASE-1 in M2a and their potential impact on tumor growth.