NMAAP1 Expressed in BCG-Activated Macrophage Promotes M1 Macrophage Polarization

Abstract

Macrophages are divided into two subpopulations: classically activated macrophages (M1) and alternatively activated macrophages (M2). BCG (Bacilli Calmette-Guérin) activates disabled naïve macrophages to M1 macrophages, which act as inflammatory, microbicidal and tumoricidal cells through cell-cell contact and/or the release of soluble factors. Various transcription factors and signaling pathways are involved in the regulation of macrophage activation and polarization. We discovered that BCG-activated macrophages (BAM) expressed a new molecule, and we named it Novel Macrophage Activated Associated Protein 1 (NMAAP1).The current study found that the overexpression of NMAAP1 in macrophages results in M1 polarization with increased expression levels of M1 genes, such as inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), Interleukin 6 (IL-6), Interleukin 12 (IL-12), Monocyte chemoattractant protein-1 (MCP-1) and Interleukin-1 beta (IL-1β), and decreased expression of some M2 genes, such as Kruppel-like factor 4 (KLF4) and suppressor of cytokine signaling 1 (SOCS1), but not other M2 genes, including arginase-1 (Arg-1), Interleukin (IL-10), transforming growth factor beta (TGF-β) and found in inflammatory zone 1 (Fizz1). Moreover, NMAAP1 overexpression in the RAW264.7 cell line increased cytotoxicity against MCA207 tumor cells, which depends on increased inflammatory cytokines rather than cell-cell contact. NMAAP1 also substantially enhanced the phagocytic ability of macrophages, which implies that NMAAP1 promoted macrophage adhesive and clearance activities. Our results indicate that NMAAP1 is an essential molecule that modulates macrophages phenotype and plays an important role in macrophage tumoricidal functions.

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Macrophage-Regulatory T Cell Interactions Promote Type 2 Immune Homeostasis Through Resistin-Like Molecule α

“…These studies highlight the complexity and importance of these cells in response to infection and inflammation (55,57), but also reveal their role in immune homeostasis (1,2,58,59). Peritoneal macrophages follow similar activation pathways to other macrophage lineages, where M1 macrophages activated by IFNg and TNFa have enhanced microbicidal or tumoricidal capacity and secrete high levels of pro-inflammatory cytokines and mediators (60), while IL-4 activated M2 macrophages reduce inflammation and contribute to tissue repair through secretion of IL-10 and TGF-b (61,62). Although M2 macrophages have antiinflammatory roles, dysregulation of these signaling pathways also induce inflammation and immunopathology (38), which we investigated using the in vivo model of IL-4c induced peritonitis.…”

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“…Macrophages are often classified as the classically activated M1 type and alternatively activated M2 type based on cell functions. M1 macrophages are primarily stimulated by lipopolysaccharide (LPS) or IFN-γ ( 16 ) and possess high antigen-presenting capabilities ( 17 ), which are characterized by the high secretion of pro-inflammatory cytokines, such as IL-6, IL-12, IL-23 and TNF-α ( 18 ), to promote a Th1 response, and microbicidal and tumoricidal activities ( 19 ). M2 macrophages are polarized via IL-4, IL-10, and IL-13 and exhibit a weak antigen-presenting ability ( 20 ).…”