Research Article: Negative Immune Regulator TIPE2 Promotes M2 Macrophage Differentiation through the Activation of PI3K-AKT Signaling Pathway

Date Published: January 25, 2017

Publisher: Public Library of Science

Author(s): Ruiling Liu, Tingting Fan, Wenwen Geng, Youhai H. Chen, Qingguo Ruan, Cui Zhang, Marco Falasca.

http://doi.org/10.1371/journal.pone.0170666

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.

Partial Text

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 activated macrophages (M1) and alternatively activated macrophages (M2) [5]. Th1-related cytokines like IFN-γ/TNF-α, endogenous stress signals and exogenous stimuli such as LPS (lipopolysaccharides) and dsDNA will polarize macrophages towards an M1 phenotype. In contrast, Th2-related cytokines like IL-4/IL-13 and immunomodulatory cytokines IL-10/TGF-β will polarize macrophages towards an M2 phenotype [6, 7]. In addition, it has been reported that glucocorticoid hormones, apoptotic cells and immune complexes can also induce macrophages to an M2-like phenotype [8, 9]. M1 macrophages can secrete inflammatory cytokines such as IL-1β, TNF-α, IL-12, IL-18 and IL-23 [10–12]. They have also been shown to up-regulate the expression of the intracellular protein suppressor of cytokine signaling 3 (SOCS3) [13, 14] and promote the production of NO from L-arginine through the activation of inducible nitric oxide synthase (iNOS) [15, 16]. Although M1 macrophages play important roles in the promotion of Th1 responses and mediate resistance to pathogens, they have also been implicated in initiating and sustaining inflammation, and therefore can also be detrimental to health [17, 18]. M2 macrophages are able to secrete high amounts of immunomodulatory cytokines such as IL-10 and TGF-β and convert arginine metabolism to express ornithine and polyamine [19]. M2 macrophages possess anti-inflammatory functions and are able to promote tissue remodeling and repair, dampen inflammation, help in the clearance of parasites and enhance tumor progression [20–22].

Previously it has been shown that TIPE2 is a negative regulator of type 1 innate and adaptive immune response [23]. Following LPS challenge, TIPE2 negatively regulates inflammation by switching arginine metabolism from nitric oxide synthase to arginase in macrophages [26]. These results indicate that TIPE2 may play an important role during macrophage differentiation. Depending on the microenvironment stimuli, macrophages can differentiate into M1 or M2 macrophages in vivo [32]. In vitro, M1 macrophages can also be induced by IFN-γ and LPS while M2 macrophages can be induced by Th2 cytokines such as IL-4 and IL-13 [33]. Those in vitro induced macrophages have been widely used to study the function of macrophages since they share the same phenotype and function as in vivo polarized macrophages. Our results showed that TIPE2 inhibits IFN-γ and LPS induced M1 macrophage differentiation in vitro. This could be due to the inhibition of NF-κB and MAPK signaling pathway by TIPE2 based on published data [23]. Furthermore, we found that Tipe2-deficient bone-marrow cells are defective in IL-4-induced M2 macrophage differentiation in vitro, which is consistent with a recently published paper showing that TIPE2 overexpression induced macrophage polarization to a M2 phenotype [28].

TIPE family member TIPE2 can promote the activation of PI3K-AKT signaling pathway, which leads to enhanced M2 macrophage differentiation. Thus, the importance of TIPE2 in controlling type 1 inflammation may result from its role in switching macrophage differentiation from classically activated M1 macrophages to alternatively activated M2 macrophages.

 

Source:

http://doi.org/10.1371/journal.pone.0170666

 

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