Georgia Cancer Center, Augusta University, Augusta, GA.
Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA.
J Immunol. 2023 Sep 1;211(5):853-861. doi: 10.4049/jimmunol.2200909.
APCs such as dendritic cells and macrophages play a pivotal role in mediating immune tolerance and restoring intestinal immune homeostasis by limiting inflammatory responses against commensal bacteria. However, cell-intrinsic molecular regulators critical for programming intestinal APCs to a regulatory state rather than an inflammatory state are unknown. In this study, we report that the transcription factor retinoid X receptor α (RXRα) signaling in CD11c+ APCs is essential for suppressing intestinal inflammation by imparting an anti-inflammatory phenotype. Using a mouse model of ulcerative colitis, we demonstrated that targeted deletion of RXRα in CD11c+ APCs in mice resulted in the loss of T cell homeostasis with enhanced intestinal inflammation and increased histopathological severity of colonic tissue. This was due to the increased production of proinflammatory cytokines that drive Th1/Th17 responses and decreased expression of immune-regulatory factors that promote regulatory T cell differentiation in the colon. Consistent with these findings, pharmacological activation of the RXRα pathway alleviated colitis severity in mice by suppressing the expression of inflammatory cytokines and limiting Th1/Th17 cell differentiation. These findings identify an essential role for RXRα in APCs in regulating intestinal immune homeostasis and inflammation. Thus, manipulating the RXRα pathway could provide novel opportunities for enhancing regulatory responses and dampening colonic inflammation.
树突状细胞和巨噬细胞等 APC 对于调节免疫耐受和恢复肠道免疫稳态至关重要，其通过限制对共生菌的炎症反应来实现。然而，将肠道 APC 编程为调节状态而不是炎症状态的细胞内分子调节因子尚不清楚。在本研究中，我们报告了 CD11c+ APC 中的转录因子视黄酸受体 X 受体α（RXRα）信号对于通过赋予抗炎表型来抑制肠道炎症是必需的。使用溃疡性结肠炎小鼠模型，我们证明了靶向敲除 CD11c+ APC 中的 RXRα 会导致 T 细胞稳态丧失，从而导致肠道炎症增强和结肠组织的组织病理学严重程度增加。这是由于促炎细胞因子的产生增加，这些细胞因子驱动 Th1/Th17 反应，以及免疫调节因子的表达减少，这些因子促进了结肠中调节性 T 细胞的分化。与这些发现一致，通过抑制炎症细胞因子的表达和限制 Th1/Th17 细胞分化，RXRα 途径的药理学激活减轻了小鼠的结肠炎严重程度。这些发现确定了 RXRα 在 APC 中调节肠道免疫稳态和炎症的重要作用。因此，操纵 RXRα 途径可能为增强调节反应和抑制结肠炎症提供新的机会。
