Table 1.
Macrophage receptor-ligand interaction signaling pathways, biological benefits, and preclinical/clinical trials.
| Regulatory Types | Receptor-Ligand | Receptor Categories | Major Receptor Distribution | Signaling Pathways | Macrophage Polarization | Biological Effects | Preclinical/Clinical Studies | References |
|---|---|---|---|---|---|---|---|---|
| Recruitment Regulation | CCR2- CCL2 | GPCR | monocyte、Macrophage | PI3K/Akt;MAPK: ERK1/2、JNK、p38;NF-κB | Induction of M1-type Macrophage Polarization | Promoting M1 Macrophage Formation and Migration; Inducing Inflammatory Response and Tissue Damage. | Inhibition of CCR2 suppresses recruitment of inflammatory monocytes (precursors of M1 Macrophages) and slows the progression of DMD | (81) |
| CCR5- CCL5 | GPCR | T cells、Macrophage、DC | PI3K/Akt;MAPK:ERK1/2、JNK、p38;NF-κB | Induction of M1-type Macrophage Polarization | Recruitment and Accumulation of Blood Monocytes | Oral CCR5 antagonist AZD5672 shows no clinical benefit in the treatment of RA | (82) | |
| CSF1R- CSF | Single-pass Transmembrane Receptor of RTK | Macrophage | PI3K/Akt、MAPK:ERK1/2、JNK和p38、JAK/STAT | Induction of M1-type Macrophage Polarization | M1 Pro-inflammatory Macrophage Infiltration as a Major Cause of Musculoskeletal Tissue Damage | Clinical efficacy observed with pexidartinib, a CSF1R inhibitor, in the treatment of tenosynovial giant cell tumor, with an ORR of 39% | (83) | |
| IL10R- IL10 | Transmembrane Proteins of Type II Cytokine Receptor Family | Macrophage、T cells、NKC | JAK/STAT | Induction of M2-type Macrophage, Inhibition of M1-type Macrophage Activation | Anti-inflammatory and Immune-regulatory Functions; Maintaining Immune Homeostasis | Reduction in macrophage infiltration, inhibition of immune cell migration to inflammatory sites, and suppression of inflammation contribute to tissue damage attenuation | (84) | |
| TGFβR-TGFβ | RSK Family Receptors | Macrophage、T cells、B cells | Smad、MAPK、PI3K/Akt.etc | Induction of M2-type Macrophage, Inhibition of M1-type Macrophage Activation | Dual Role of TGFβ in Inhibiting or Suppressing Immune Damage | Importance of monocyte recruitment in the generation of M1 pro-inflammatory macrophages | (85) | |
| IL1a/βR- IL1a/β | Transmembrane Proteins of Type I Cytokine Receptor Family | MyD88-Dependent Pathway | Induction of M2-type Macrophage, Inhibition of M1-type Macrophage Activation | Strong Pro-inflammatory Effects; Potential Uncontrolled Inflammatory Response and Tissue Damage | Limited therapeutic effect as a monotherapy in treating knee osteoarthritis with synovitis | (86) | ||
| Phagocytic Checkpoints | SIRPα- CD47 | Transmembrane Proteins of Immunoglobulin Superfamily | Macrophage、DC、neuron | SHP-1 and SHP-2 PTP Pathway via ITIM | Indirect Effects on Macrophage Polarization | Decreasing Macrophage Phagocytic Activity in the Immune Microenvironment | Inhibition of macrophage phagocytosis of erythrocytes; increased macrophage clearance of apoptotic cells by blocking ITIM pathway | (87) |
| SIGLEC10- CD24- | CD24:Glycoprotein SIGLEC10:Transmembrane Glycoprotein of the Immunoglobulin Superfamily |
CD24:广泛分布 SIGLEC10:Macrophage、DC、B cells |
SHP-1 and SHP-2 PTP Pathway via ITIM | Indirect Effects on Macrophage Polarization | Anti-phagocytic, Inhibition of Immune Cell Activation; Prevention of Immune Cell Overactivation | \ | (88) | |
| GPR84-APMAP | GPCR | Macrophage、Neutrophils | \ | Induction of M1-type Macrophage Polarization | Decreasing Macrophage Phagocytic Activity in the Immune Microenvironment | Loss of APMAP expression enhances phagocytic function, promotes apoptotic cell engulfment, suppresses autoimmune reactions triggered by antigen presentation, and restricts immune-inflammatory damage | (89) | |
| LILRB1-MHC I | Inhibitory Receptors of the Leukocyte Immunoglobulin-like Receptor Family | Macrophage、monocyte、DC | SHP-1 and SHP-2 PTP Pathway via ITIM | Indirect Effects on Macrophage Polarization | Inhibiting Macrophage Activation, Reducing Activity in the Immune Microenvironment, Preventing Immune Cell Overactivation, Maintaining Tissue Homeostasis | \ | (90) | |
| Immune Stimulation | PRRs-PAMP/DAMP | TLRs、CLRs、NLRs、RLRs | Macrophage、DC | TLRs, CLRs: NF-κB and IRF Signaling Pathways; NLRs and RLRs : Caspase-1 Pathway | Induction of M1-type Macrophage Polarization | Induction of Inflammatory Cytokines and Type I Interferon Production | Overactivation of PRRs may lead to immune damage | (91) |
| TLR4- LPS/DAMP | Macrophage、DC、Neutrophils | MyD88-Dependent Pathway: NF-κB and MAPK Pathways; TRIFDependent Pathway: IRF3 and NF-κB Pathways | Induction of M1-type Macrophage Polarization | Strong Inflammatory Response and Antipathogenic Ability; Persistent Activation of TLR4 Signaling May Lead to Uncontrolled Inflammatory Response | Humanized anti-TLR4 monoclonal antibody Paridiprubart shows potential for rheumatoid arthritis research by promoting macrophage apoptosis and inhibiting Th1 response | (92) | ||
| TNFR- TNF | TNFR1 Widely distributed、TNFR2:Macrophag、endothelial cells. | TNFR1 Activation of Downstream NF-κB, MAPK, PI3K/Akt, and JNK Signaling Pathways | Induction of M1-type Macrophage Polarization | Inducing Inflammatory Response, Causing Immune Damage | Anti-TNF drugs reduce concentrations of matrix metalloproteinases MMP-1 and MMP-3, cartilage and synovial proliferation, acute phase inflammation markers CRP and ESR, pro-inflammatory cytokine production in monocyte-derived macrophages, and increase phagocytic function | (93) | ||
| CD40- CD40L | CD40L/CD40Transmembrane Glycoprotein, Member of the Tumor Necrosis Factor (TNF) Family | CD40L、CD40:T cells、B cells、Macrophage、DC. | NF-κB、JNK、p38 MAPK | Induction of M1-type Macrophage Polarization | Promoting Antigen Presentation Ability of Antigen-Presenting Cells, Affecting T-cell Activation and Function, Overactivation May Lead to Autoimmune Response Dysregulation and Damage to Normal Tissues | CD40L monoclonal antibody Toralizumab blocks CD40 signaling, providing protection in multiple sclerosis and potential treatment for systemic lupus erythematosus | (94) | |
| Immune Suppression | TREM2- Anionic molecules | Transmembrane Immunoglobulin, Member of the Triggering Receptor Family (TREM Family) | Macrophage、Microglial cells | Activation of SYK, PI3K/AKT, and ERK Signaling Pathways via TAM | Induction of M2-type Macrophage Polarization | Inhibiting Inflammatory Response, Suppressing Pro-inflammatory Cytokine Production in Macrophages, Increasing Arginase 1 Expression, and Expressing IFNγ to Inhibit T-cell Function, Promoting Neuroprotection and Regulating Cell Survival | In neuromuscular degenerative diseases, TREM2 plays a key role in modulating microglial function and neuroinflammation; TREM2 mutations or functional defects are closely related to the onset and progression of neurodegenerative diseases | (95) |
| MARCO- Polyanionic ligands | Transmembrane Glycoprotein, Member of the Scavenger Receptor Family | Macrophage(Especially on the surface of plasma cell like macroscopic). | Induction of M1-type Macrophage Polarization | Regulating Macrophages, Leading to Inhibition of Natural Killer Cell and T-cell Activation, and Increased Infiltration of Regulatory T-cells (Treg Cells), Exhibiting Immunosuppressive Function in the Immune Microenvironment | MARCO+ monocytes are potent effector cells for skin and lung fibrosis in SSc, with their presence correlating with disease onset and progression | (96) | ||
| SR-A— macromolecular ligand | Transmembrane Glycoprotein, Member of the Macrophage Scavenger Receptor Family | Macrophage | MAPK、NF-κB 、JAK/STAT | Induction of M1-type Macrophage Polarization | Participating in the Clearance of Endogenous Waste, Alleviating Inflammatory Response, and Inhibiting Immune Damage through Suppression of T-cell Function | SR-A plays a key role in chronic inflammatory diseases; SR-A neutralizing antibody is a potential candidate drug for improving rheumatoid arthritis-associated osteolysis | (97) | |
| TIM3- galectin 9 | Transmembrane Immunoglobulin, Member of the TIM Family | Macrophage、TC、DC、NKC、BC, | Induction of M2-type Macrophage Polarization | Inhibiting the Activation and Effector Functions of T-cells and Other Immune Cells, Limiting the Development of Chronic Inflammation and Immune Damage | TIM3 plays a crucial role in bone marrow cell-mediated inflammatory responses | (98) | ||
| Siglec- sialic acid | Transmembrane Glycoprotein, Member of the Siglec Family | Macrophage、NKC、Monocyte | ITIM-Mediated Activation of Immune Cell Inhibition Signaling Pathways | \ | Inhibiting Inflammatory Response and Cytokine Production, Reducing Neutrophil and Macrophage Migration and Chemotaxis, Regulating T-cell and Antigen-Presenting Cell Interactions, Suppressing Immune Damage | Siglec-15 exhibits multiple functions in osteoclast development, bone resorption, and T cell immunity | (99) | |
| LAIR1、LILRB2、LILRB4- MHC I | Transmembrane Glycoprotein, Member of the Immunoglobulin Superfamily | Monocyte、Macrophage、DC、B celsl | ITIM-Mediated Activation of Immune Cell Inhibition Signaling Pathways | \ | Involvement in Treg Cell Recruitment, Regulating Macrophage Function in the Immune Microenvironment, Maintaining Immune System Homeostasis, Alleviating Inflammatory Response, Preventing Overactivation of the Immune System | Overexpression of LAIR-1 in macrophages within synovial tissue of RA patients | (100) | |
| Fibrosis Regulation | PDGFR- PDGF | Tyrosine Kinase Receptor | Fibroblasts、smooth muscle cell、endothelial cells、Macrophage | Ras/MAPK、PI3K/Akt、PLCγ/PKC、STAT Pathways | Induction of M2-type Macrophage Polarization | Tissue Repair, Angiogenesis, Inflammatory Response, Tumor Growth, Inducing Fibrosis | Under fibrotic conditions, transforming growth factor β (TGF-β) is enhanced, while platelet-derived growth factor (PDGF) signaling is upregulated in regenerative conditions | (101) |
| IL33R-IL33 | IL-1 Family Members | Multiple cell types | Activation of MyD88-Dependent Signaling Pathways, Activating NF-κB and MAPK Pathways | Induction of M2-type Macrophage Polarization | Recruiting and Regulating Inflammatory Cell Function, Producing Pro-fibrotic Cytokines IL-13 and TGF-β1, Leading to Pathological Fibrosis Development | Polarized M2 macrophages produce IL-13 and TGF-β1, enhancing profibrotic cytokine production and promoting fibrosis onset and progression | (102) | |
| PPAR- steroid | Nuclear Receptor | Expressed in multiple tissues and cell types | PPARs Binding with Nuclear Receptor RXR, Regulating Target Gene Expression through PPRE | Induction of M2-type Macrophage Polarization | Directly Regulating Macrophage Activation without Affecting Infiltration, Effectively Counteracting Inflammation and Fibrosis Disease Progression | PPAR agonists effectively counteract inflammation and disease progression, improving tissue inflammation and fibrosis | (103) | |
| CCR2-CCL2 | GPCR | Monocyte、Macrophage、T cell subpopulations (Th1, Th17) | PI3K/Akt、MAPK、PLC/PKC、Rho GTPase Pathways | Inducing macrophages to polarize toward M2 phenotype to some extent | Inducing Macrophage Accumulation in Damaged Tissue; Macrophage Infiltration Exacerbating Inflammatory Response, Leading to Fibrosis Development | In some fibrotic diseases, CCL2/CCR2 signaling has been implicated in the pathological process, and its inhibition has therapeutic potential | (104) | |
| TGFβR-TGFβ | Membrane-bound Receptor | Macrophage、T cells和B cells、epithelial cells、Fibroblasts | Smad、MAPK、PI3K/Akt、Rho GTPase Pathways | \ | Activating Macrophages and Inducing Fibroblasts to Transition to a Pro-fibrotic Activated State | Consistent antifibrotic activity of TGFβ-blocking agent pirfenidone in various animal models | (105) | |
| Frizzled protein、LRP5/6- Wnt protein | Frizzled protein:GPCR、LRP5/6:Low-Density Lipoprotein Receptor-Related Protein | Widely distributed | Canonical、non-canonical Pathways、Wnt Pathways | Induction of M2-type Macrophage Polarization | Wnt pathway activation closely associated with EMT, activation of fibroblasts, and extracellular matrix deposition | Drugs and small molecule inhibitors targeting the Wnt signaling pathway have shown therapeutic effects in animal models of fibrotic diseases; inhibition of Wnt signaling has antifibrotic therapeutic potential | (106) |
GPCR, G protein-coupled receptor; RXR: Retinoid X receptor; RTK, Tyrosine kinase-like receptor; canonical:β-catenin-dependent non-canonical:β- Chain protein independence; NLRs, Nucleic acid-sensing receptors; EMT, epithelial-mesenchymal transition; CLRs, C-type lectin-like receptors; DMD, Duchenne Muscular Dystrophy; SR A, Scavenger Receptor A; RSK, serine/threonine kinase receptor; RLRs, RIG-I-like receptors; TLRs, Toll-like receptors; ITIM, Immunoreceptor tyrosine-based inhibitory motif.