Macrophage Polarization Signaling Pathway

Macrophages are tissue-resident professional phagocytes, which play an important role in immune-regulation. Activated macrophages are routinely classified into two different types: M1macrophages (classic activation) and M2macrophages (alternative activation). M1 macrophages are pro-inflammatory and have a central role in host defense against infection, while M2 macrophages are associated with responses to anti-inflammatory reactions and tissue remodeling, and they represent two terminals of the full spectrum of macrophage activation. M1–M2 polarization of macrophage is a tightly controlled process entailing a set of signaling pathways, transcriptional and posttranscriptional regulatory networks.

M1 stimuli

M1 phenotype of macrophage is stimulated by microbial products or pro-inflammatory cytokines. Interferon-γ (IFN-γ) is the main the cytokine produced form Th1 cells that polarizes macrophages toward theM1 phenotype. IFN-γ receptor is formed of the IFNGR and IFNAR chains. The receptor recruits Janus kinase (Jak) 1 and Jak2 adaptors which further lead to the activation of STAT1 (signal transducers and activators of transcription 1). IFN-γ triggers the expression programs of specific gene including Major Histocompatibility Complex (MHC) II, interleukin (IL)-12, nitric oxide synthase2 (NOS2) and suppressor of cytokine signaling (SOCS)1.IFN-γ is involved in combination with LPS in the M1/M2 paradigm. However, the gene expression profiles of the combination are different from lipopolysaccharide (LPS) or IFN-γ profiles alone.

Bacterial moieties arerecognized by pattern recognition receptors, such as Toll like receptors (TLRs). Particularly, TLR4 can be stimulated by LPS and other microbial ligands. TLR4 activation induces TIR-domain-containing adapter-inducing interferon-β (TRIF) and Myeloid differentiation primary response 88 (MyD88)pathways. TRIF mediated pathway causes the activation of a cascade of kinases, which finally leads to the activation oftranscription factor interferon-responsive factor 3 (IRF3). IRF3 controls the production and secretion of type I interferon, including IFNα and IFNβ. Secreted type 1 interferons bind to IFNAR with consequent activation of the transcription factor STAT1. MyD88, the other adaptor in responding to TLR4 activation, triggers the nuclear factor kappa B (NF-kB) pathway (p65 and p50), which is a key transcription factor related to M1 macrophage polarization. In addition, MyD88 activates activator protein 1 (AP-1) via MAPK signaling. These pathways regulate a huge number of inflammatory genes including pro-inflammatory cytokines (such as tumor necrosis factor (TNF), and IL-1β, IL-6, and IL-12), chemokines (such as chemokine [C-C motif] ligand 2 CCL2, chemokine [C-X-C motif] ligand 10 [CXCL10], and CXCL11), co-stimulatory molecules, and antigen-processing molecules.Cytokines secreted from activated macrophage or other cells bind to cytokine receptors, and share pro-inflammatory properties have been termed M1 phenotype.

M2 stimuli

IL-4 (Th2 produced cytokine) and IL-13 bind to the receptor IL-4Rα, whichpromotes the M2 polarization though several pathways, typicallyJAK1 and JAK3 signaling which further causing the activation and translocation of STAT6. Other transcription factors involved include IRF4 and peroxisome proliferator activated receptor γ (PPARγ). STAT6, IRF4 and PPARγ regulate many of the genes associated with mouse M2 macrophages, such as arginase 1 (Arg1), CD206 (or macrophage mannose receptor 1, Mrc1), resistin-like-α (Retnla or Fizz1) and Ym1 (or chitinase 3-like 3, Chi3l3). Transcription factor PPARγ can also be activated through the binding of free fatty acids to fatty acid receptors.

IL-10 can be produced by all leukocytes. It binds the IL-10 receptor, a heterodimer of IL10R1 and IL10R2. Ligation of IL-10R with IL-10 leads to the receptor autophosphorylation,evoking the activation of the transcription factor STAT3. The binding of STAT3 up-regulates the expression of SOCS3, which mediates the suppression of pro-inflammatory cytokine signaling pathways.

Glucocorticoids are generated from the glucocorticoid hormones as a result from metabolism by cellular enzymes in macrophages. They are lipophilic, and can diffuse through the membrane. Intracellular glucocorticoids bind the glucocorticoid receptor (GR), furtherresulting in the nuclear translocation of the complex. The complex directly binds DNA, promoting the transcription of anti-inflammatory genes such as IL-10 and IL1R2. Alternatively, GR complex can also interact with other transcription factors like NF-kB or AP-1.


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