C-C motif chemokine ligand 2–Mitogen-activated protein kinase–Nuclear factor kappa-light-chain-enhancer of activated B cells–Signal transducer and activator of transcription 3 inflammatory pathway (CCL2–MAPK–NF-κB–STAT3 pathway)

The C-C motif chemokine ligand 2–Mitogen-activated protein kinase–Nuclear factor kappa-light-chain-enhancer of activated B cells–Signal transducer and activator of transcription 3 (CCL2–MAPK–NF-κB–STAT3) inflammatory pathway is a multi-node signaling axis central to the regulation of the innate immune response and chronic inflammation (PMID: 28651314). The pathway is initiated by the binding of the chemokine CCL2 (also known as Monocyte Chemoattractant Protein-1 or MCP-1) to its cognate G protein-coupled receptor, CCR2, which triggers the activation of the mitogen-activated protein kinase (MAPK) family, including ERK1/2, JNK, and p38 (PMID: 31254585). These kinases subsequently phosphorylate and activate the transcription factors NF-κB and STAT3, which translocate to the nucleus to induce the expression of pro-inflammatory cytokines, anti-apoptotic genes, and matrix metalloproteinases (PMID: 25893295). This signaling cascade is a major driver of monocyte/macrophage recruitment and polarization, contributing significantly to the pathogenesis of various cancers, neuropathic pain, and autoimmune disorders (PMID: 30107416). In the tumor microenvironment, the activation of this axis promotes tumor cell proliferation, epithelial-mesenchymal transition (EMT), and the creation of an immunosuppressive niche (PMID: 28651314). Therapeutic interventions targeting this pathway include monoclonal antibodies against CCL2, small molecule CCR2 antagonists, and inhibitors of the downstream kinase and transcription factor components (PMID: 24033861). Systemic inhibition of such fundamental signaling nodes often presents significant safety challenges, including impaired host defense and off-target toxicities (PMID: 24033861).

Other names

MCP-1/MAPK/NF-κB/STAT3 axisCCL2-CCR2 signaling cascadeCCL2-mediated inflammatory pathway

Inhibition of ligand-receptor binding (CCL2/CCR2), inhibition of kinase phosphorylation (MAPK), or blockade of transcription factor activation and nuclear translocation (NF-κB/STAT3).