Kapoor Nidhi, Niu Jianli, Saad Yasser, Kumar Sanjay, Sirakova Tatiana, Becerra Edilu, Li Xiaoman, Kolattukudy Pappachan E
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816.
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816
J Immunol. 2015 Jun 15;194(12):6011-23. doi: 10.4049/jimmunol.1402797. Epub 2015 May 1.
Macrophage polarization plays a critical role in tissue homeostasis, disease pathogenesis, and inflammation and its resolution. IL-4-induced macrophage polarization involves induction of STAT6 and Krüppel-like factor 4 (KLF4), which induce each other and promote M2 polarization. However, how these transcription factors implement M2 polarization is not understood. We report that in murine macrophages MCP-1-induced protein (MCPIP), induced by KLF4, inhibits M1 polarization by inhibiting NF-κB activation and implements M2 polarization using both its deubiquitinase and RNase activities that cause sequential induction of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and autophagy required for M2 polarization. MCPIP also induces C/EBPβ and PPARγ, which promote M2 polarization. Macrophages from mice with myeloid-targeted overexpression of MCPIP show elevated expression of M2 markers and reduced response to LPS, whereas macrophages from mice with myeloid-specific deletion of MCPIP manifest elevated M1 polarization with enhanced phagocytic activity. Thus, both in vivo and in vitro experiments demonstrate that the transcription factors STAT6 and KLF4 implement IL-4-induced M2 polarization via the dual catalytic activities of MCPIP.
巨噬细胞极化在组织稳态、疾病发病机制、炎症及其消退过程中发挥着关键作用。白细胞介素-4（IL-4）诱导的巨噬细胞极化涉及信号转导和转录激活因子6（STAT6）和类Krüppel因子4（KLF4）的诱导，它们相互诱导并促进M2极化。然而，这些转录因子如何实现M2极化尚不清楚。我们报道，在小鼠巨噬细胞中，由KLF4诱导的单核细胞趋化蛋白-1诱导蛋白（MCPIP）通过抑制核因子κB（NF-κB）激活来抑制M1极化，并利用其去泛素酶和核糖核酸酶活性实现M2极化，这些活性导致活性氧（ROS）、内质网（ER）应激和M2极化所需的自噬的顺序诱导。MCPIP还诱导促进M2极化的C/EBPβ和过氧化物酶体增殖物激活受体γ（PPARγ）。髓系靶向过表达MCPIP的小鼠的巨噬细胞显示M2标志物表达升高，对脂多糖（LPS）的反应降低，而髓系特异性缺失MCPIP的小鼠的巨噬细胞表现出M1极化升高，吞噬活性增强。因此，体内和体外实验均表明，转录因子STAT6和KLF4通过MCPIP的双重催化活性实现IL-4诱导的M2极化。
