Fig. 2.

Mechanisms and markers of polarized macrophages in pathology. a Key signals driving M1 vs M2 polarization of macrophages. Inflammatory cytokines (IFNγ, TNFα), pathogen-associated molecular patterns (e.g., LPS), and damage-associated molecular patterns (e.g., HMGB1, HSP, Fetuin A, ATP) induce M1-polarized activation, whereas Th2 cytokines (IL-4, IL-13), anti-inflammatory molecules (IL-10, GC, AMP), and immunocomplexes (Ic) induce M2-polarized activation. IL-33 and thymic stromal lymphopoietin (TSLP) act as M2 amplifiers (asteriks). M1 and M2 signals engage signaling pathways involving different kinases (e.g., Akt1 and 2) and family of transcription factors (e.g., STATs, IRFs, NF-κB, KLFs, HIFs). Further, PPARγ and PPARδ control distinct aspects of M2 macrophage activation and the oxidative metabolism. c-Myc and c-Maf, respectively, regulate a subset of IL-4- and IL-10- inducible genes. Macrophage-polarized activation is also controlled at epigenetic levels by different miRNAs (miR-155, miR-124) and proteins involved in histone methylation and acetylation (bromodomain-containing BET proteins, JMJD3). Inflammatory cytokines (TNFα, IL-1β, IL-6, IL-12, IL-23, IL-27), Th1-recruiting chemokines (CXCL9, CXCL10, CXCL11), and the co-stimulatory receptor CD40, represent distinct markers of M1 polarization. M2 macrophages express higher levels of genes encoding anti-inflammatory cytokines (IL-10, TGFβ), Th2-recruiting chemokines (CCL17, CCL18, CCL22), c-type lectin (CD206, CD301, dectin-1), and scavenger receptors (CD163, Stabilin-1). Further, M1- and M2-polarized macrophages express distinct enzymes involved in iron and amino acid metabolism. Hence M1 macrophages exert anti-microbial activities by iron retention (ferritin, CP, DMT-1, Nramp-1) and ROS/NOS production (iNOS, gp91phox, p22phox), whereas M2 macrophages promote wound healing through iron recycling and release (Tfr, HO-1, Fpn) and polyamine production (Arg 1, Arg 2, ODC, SMO). b M1 and M2 macrophage polarization in disease. Association of M1 vs M2 macrophage polarization in distinct diseases. Dynamic reprogramming of macrophage polarization occurs during the progression of both infections (sepsis, protozoans, HIV) and cancer and mixed macrophage phenotypes can coexist (e.g., H. pylori infections). Systemic Inflammatory Response Syndrome (SIRS); Compensatory Anti-inflammatory Response Syndrome (CARS); Interferon γ (IFNγ) lipopolysaccharide (LPS) High Mobility Group Box 1 (HMGB1); Heat Shock Proteins (HSPs); glucocorticoids (GC) Adenosine monophosphate (AMP); Nuclear factor κB (NF-κB); Signal Transducer and Activator of Transcription (STAT); Interferon Regulatory Factor (IRF); Hypoxia Inducible Factor (HIF); Krüppel-like factor (KLF); peroxisome proliferator-activated receptors (PPAR); CCAAT/enhancer binding protein (C/EBP); Inducible nitric oxide synthase (iNOS); ceruloplasmin (CP); natural resistance-associated macrophage protein 1 (Nramp-1); divalent metal transporter-1 (DMT-1); Arginase (Arg); ornithine decarboxylase (ODC); spermidine oxidase (SMO); hemeoxygenase-1 (HO-1); ferroportin (Fpn); transferrin receptor (TfR)