Table 1.
Macrophage/monocyte activation markers
| Marker | Classification | Primary Function(s) | Stimulus/Receptor | Human Expression | Murine Expression |
|---|---|---|---|---|---|
| Identification | Cell expression | ||||
| CD11b (Mac-1a, Itgam) | ++ IM/MO, ± AM, + DC | cell adhesion/migration, complement-opsonized phagocytosis | ICAM-1 (CD54) | nonresolving ARDS (156) | lower in alveolar space; increased in migrated cells |
| CD11c (Itgax) | ± IM/MO, ++AM, +/++ DC | cell adhesion, associates with CD18 | ICAM-1 fibrinogen and iC3b | ++ iMO, + rMO | BAL expression higher than most tissues |
| CD68 (macrosialin) | +IM/MO, ++ AM | IC glycoprotein, specific mac expression (203), cell-cell interaction | + MO, IM, AM | good marker, but intracellular staining by flow; ++ DC | |
| F4-80 (EMR1) | +IM/MO, +/++ AM | glycoprotein coupling EC to IC signaling, signaling during tolerance/priming | downregulation by IFN-γ | 70% murine homolog, gene level only, ++ Eos | not as alveolar macrophage-specific |
| CD14 | ++ MO, + IM, ± AM | LPS-binding protein, TLR signaling, apoptotic cell receptor (182) | apoptotic cells | ++ (-CD16) = murine ++ Ly6c MO, + acute LPS | does not readily define mac subtypes in mice |
| CD16 | ++ AM, ++ iMO, + PMN | Fc receptor (FcγIII). NK cell activation, ADCC | IgG, IgG-antigen complex | ++ (and + CD14) = murine ± Ly6c MO | B cells, MO, AM, NK cells, PMN |
| Siglec F | +/++ AM, ++ Eos | inhibits Eos proliferation (30), virus/bacteria cell entry | Sialic acid | convergent paralog to Siglec-8 (human) (30) | |
| CD33 (Siglec-3) | + MO (human), + PMN (murine) | regulates fcn via glycan recognition, pathogen uptake | Sialic acid | MO and myeloid precursors | primarily on PMNs |
| Siglec 1 (Sialoadhesin, CD169) | ++ AM | recognition/phagocytosis of bacteria (182) | Sialic acid | macrophages, ?AM | |
| FcyR1 (CD64) | ++ IM/AM, + MO | phagocytosis, Ag capture, ADCC, signals through ITAM motif | IgG immune complex | 3 distinct genes (CD64A, B, C) | |
| CD115 (M-CSFR, CSF1R) | ++ MO (human iMO, rMO), +AM,IM | cell production, maturation, and fcn via M-CSF | M-CSF | ++ on iMO and rMO (58) | ++ MO, useful for microbead isolation |
| Gr-1 (Ly6g, Ly6c) | ++ MO, ± IM (Ly6c), ++ PMN (Ly6g) | precursor for IM (Ly6c++ MO) and AM, AAM? (Ly6+/−) | Ly6c− monocyte; Ly6g− neutrophil; Gr-1 both | ||
| 7/4 | ++MO (+ CCR2, ± CX3CR1), +PMN | ? inflammatory response | |||
| CD62L (L-selectin) | ++ iMO (also ++ Ly6c), ++ PMN | monocyte recruitment, tethering and rolling | glycoproteins (CD34, GYLCAM1, MADCAM1) | present on iMO | |
| CX3CR1 | ++MO, +AM/IM | migration, survival signal (96), patrolling (8) | CX3CL1 | Ly6C++ = rMO human; Ly6c− = iMO human | |
| M1 activation | M1 (CAM) | Microbicidal, tissue damage, cellular immunity | TNF-α, IL-12, IFN-γ | ||
| MHC II (I-A/I-E, HLA-DR) | ++ rMO, + iMO, also ++ DC | Antigen presentation | IFN-γ, but also IL-4/13 | HLA-DR: + iMO, ++ rMO, ++ resolve ARDS (156) | + IM, stimulated AM expression |
| CD80 | T-cell / PMN signaling | IFN-γ | |||
| CD86 | also + DC | T-cell / PMN signaling | IFN-γ | ++ rMO, + iMO (distinct from murine) | may be distinct than human effect |
| iNOS (Nos2) | produce NO, kill bacteria | minimal in AM | |||
| Cox2 (Ptgs2) | inflammation and pain | ||||
| IL-12 | Induces Th1 T-cell, M1 stimulus | IFN-γ | |||
| CCL15 | chemoattractant for MO, lymphs, and Eos | ||||
| CCL20 | chemoattractant for T cells | ||||
| CXCL9 | T-cell trafficking | ||||
| CXCL10 (IP-10) | induces Th1 T cells, NK cells | ||||
| IL23a (IL23p19) | enhances IFN-γ by memory T cells and induces IL-17 by Th17 cells. | ||||
| CXCL11 | inductes Th1 T cells, NK cells | ||||
| CCR2 | Ex. macrophages and monocytes | lung migration, deficiency impairs ++Ly6c MO | MCP-1 (CCL2), CCL7 | + iMO | |
| CCR5 | Ex. macrophages and monocytes | rercuitment into or within inflamed tissues (56) | CCL3, CCL5, inhibited by IL-10 (56) | + rMO | |
| 27E10 (MRP8/MRP14) | + human IM/MO | migration and adhesion, chemotactic for PMNs | nonresolving ARDS (156) | ||
| MARCO | ++AM, nonspecific for M1 | scavenger receptor, particulate ingestion (titanium dioxide) (182) | TLR signaling, microbial stimuli | expressed by steady-state AM | |
| CD36 | ++ AM, nonspecific for M1 | apoptotic cell clearance, primarily LDL uptake | IFN-γ | ||
| M2 activation | M2 (AAM) | Tissue repair, humoral immunity, allergic response | IL-4, IL-13, IL-10 | ||
| Mannose receptor (Mrc1,CD206) | also + DC (myeloid), −MO/PMN | phagocytosis of ligands (MPO, HIV Ag, bacteria (56), present Ag | downregulated by IFN-γ | ||
| Scavenger receptor A (CD204) | −MO and + DC subsets | apoptotic cell clearance | M-CSF | ||
| Dectin-1 | β-glucan receptor, TLR2 interaction (182), phagocytosis, proliferate T cells | ||||
| IL-4ra | IL-4/IL-13 signaling | IL-10 (56), + feedback with IL-4/13 | |||
| Arg1 | counteracts Nos2 (iNO) (56) | induced by IFN-γ/STAT3 too (56) | Not upregulated | ||
| 12,15-lipoxygenase (LOX) | mediates PPARγ upregulation by IL-4 | ||||
| TfR (CD71) (79) | carrier protein for transferrin, iron uptake, cell proliferation | ||||
| OX2R (CD200R) | bind epithelial CD200 to dampen AM inflammation | mainly IL-10, TGF-β | |||
| IL-10 | not specific, ?Mreg subpopulation | deactivate resp. burst and TNF-α, ? fibrogenesis | TLR activation | ||
| TGF-b | key role in fibrosis | IL-13 (56) | |||
| IL-1ra (IL-1 decoy receptor) | Anti-IL-1 effects | Expressed by Gr-1+CCR2+ ex. Macs (64) | |||
| Cxcl13 | B cell chemoattractant | ||||
| CCL12 | monocyte chemoattactant, recruitment of fibrocytes | ||||
| CCL17 (TARC) | binds CCR4, ++ MO, ++ DC | drives fibrogenesis with IL-10, acts on CCR4+ subset of CD4 T cells (56) | IL-4/IFN-γ antagonistic; STAT6/1-binding (56) | ||
| CCL18 (AMAC1) | also + DC | attracts lymphocytes, monocytes | IL-10 | ||
| CCL22 (MDC) | attracts CCR4+ Th cells to polarize Th2 response | downregulated by IFN-γ and IL-10 | |||
| CCL24 | chemoattractant for eosinophils, mast cells and basophils | ||||
| YM1 (Chi3l3) | IC staining by flow cytometry | chitinase-like protein, binds to ECM, heparan sulfate | IL-4/IFN-γ antagonistic; STAT6/1-binding (56) | ||
| RELMa (Fizz1) | IC staining by flow cytometry | resistin-like secreted protein (56), promote ECM deposition | IL-4/IFN-γ antagonistic; STAT6/1-binding (56) | Not expressed | + Eos, epithelial cells |
| Mac-2 (galectin-3) | ++MO, AM | CD98 binding activates PI3K, + feedback loop with IL-4 | Inhibited by LPS | ||
| 25F9 | resident macs | late inflammatory macrophage | ++ resolving ARDS (156) | ||
| RM3/1 | ++ MO, AM, CD163 family | membrane glycoprotein, late inflammatory macrophage | ++ resolving ARDS (156) |
Identification of macrophage/monocyte markers and activation states, including primary function, key stimuli/receptor, and known details about human or murine expression. Top: identification of macrophage and monocyte subpopulations in mice and humans are based on single or multiple combinations of surface and intracellular markers. We present correlative data on human leukocyte expression for each marker. Middle: surface and intracellular markers of M1 macrophage activation, along with primary function in addition to general characteristics including microbiocidal activity, tissue damage, and cellular immunity. Transcription factors that promote an M1 activated phenotype include NF-κB, IRF5, STAT1. Stimuli common to the group include IFN-γ, TNF-α, and IL-12. Bottom: surface and intracellular markers of M2 macrophage activation, along with primary function in addition to general characteristics including wound healing, tissue repair, humoral immunity, and allergic response. Transcription factors that promote an M2-activated phenotype include IRF4, KLF4, PPAR, and STAT6. Stimuli common to the group include IL-4, IL-13, and IL-10, although some consider IL-10 programmed macrophages to behave as a distinct, regulatory phenotype (MReg).
AAM, alternatively activated macrophage (M2); ADCC, antibody-dependent cell-mediated cytotoxicity; Ag, antigen; AM, mature alveolar macrophages; ARDS, acute respiratory distress syndrome; BAL, bronchoalveolar lavage; CAM, classically activated macrophage (M1); Cox2, cyclooxygenase-II enzyme; CSF, colony stimulating factor; CX3CL1, fractaline; CX3CR1, CX3C chemokine receptor 1; DC, dendritic cell; EC, extracellular; ECM, extracellular matrix; Eos, eosinophil; Ex., exudative; fcn, function; FcRγ1, high-affinity Fc γ receptor; HLA, human leukocyte antigen; IC, intracellular; ICAM-1, intercellular adhesion molecule 1; IL-4ra, IL-4 receptor α; IM, immature alveolar macrophage/interstitial macrophages; iMO, human inflammatory (classical) monocyte; iNOS, inducible nitric oxide synthase; IP-10, interferon γ-induced protein 10; ITAM, immune-receptor tyrosine activation motif; Itgam, integrin αM; Itgax, integrin αX; LPS, lipopolysaccharide (endotoxin); LDL, low-density lipoprotein; mac, macrophage; MARCO, macrophage receptor collagenous domain; M-CSF, macrophage colony-stimulating factor; MHC, major histocompatibility complex; MO, monocyte; MReg, regulatory macrophage, possible subset of AAM; NK, natural killer; PMN, neutrophil; PPAR, peroxisome proliferator-activated receptor; rMO, human resident (nonclassical; intermediate) monocyte; siglec, sialic acid-binding immunoglobulin-type lectins; TfR, transferrin receptor; TLR, Toll-like receptor; 27E10, calgranulin A/B.