Abstract
Macrophages play important roles in the regulation of the innate and adaptive immune responses. Classically activated macrophages and alternatively activated macrophages are the two major forms of macrophages and have opposing functionalities. Tumor necrosis factor-α-induced protein 8–2 is expressed primarily by immune cells and negatively regulates type 1 innate and adaptive immune responses to maintain immune tolerance. While previous studies indicate that TIPE2 promotes M2 but inhibits M1 macrophage differentiation, the underlying molecular mechanism by which TIPE2 promotes M2 macrophage differentiation remains unclear. Our current study shows that TIPE2-deficient bone-marrow cells are defective in IL-4 induced M2 macrophage differentiation in vitro. Mechanistic studies revealed that TIPE2 promotes phosphoinositide metabolism and the activation of the down-stream AKT signaling pathway, which in turn leads to the expression of markers specific for M2 macrophages. In addition, our results showed that Tipe2-deficiency does not affect the activation of the JAK-STAT6 signaling pathway that also plays an important role during M2 macrophage differentiation. Taken together, these results indicate that TIPE2 promotes M2 macrophage differentiation through the activation of PI3K-AKT signaling pathway, and may play an important role during the resolution of inflammation, parasite control, as well as tissue repair.
Highlights
Macrophages play important roles in the regulation of the immune response and are involved in health and disease [1, 2]
In order to explore the role of Tumor necrosis factor-α induced protein-8-like 2 (TIPE2) in macrophage differentiation, bone marrow derived macrophages (BMM) from wild-type and Tipe2-deficient mice were treated with either IFN-γ plus LPS to induce M1 macrophages or IL-4 to induce M2 macrophages
Our results showed that Tipe2-deficient macrophages produced more IL-12 than WT macrophages under M1 macrophage-inducing condition (Fig 1C)
Summary
Macrophages play important roles in the regulation of the immune response and are involved in health and disease [1, 2]. The main function of macrophages is to respond to pathogens and regulate the immune response through antigen presentation and cytokine production [3, 4]. Depending on the micro-environmental stimuli, macrophages can differentiate into classically. TIPE2 Promotes the Activation of PI3K-AKT Signaling Pathway received the funding: YHC. Grant numbers: JCYJ20140610151856705, JCYJ20150630114942263 Author received the funding: QR. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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