Tissue-resident innate immune cells derived from monocytes that perform phagocytosis, antigen presentation, cytokine production, and tissue remodeling. Macrophages exhibit functional polarization into M1 (pro-inflammatory) and M2 (anti-inflammatory/tissue repair) phenotypes depending on microenvironmental signals.
Macrophages express pattern recognition receptors (TLRs, NOD-like receptors) that detect PAMPs and DAMPs, triggering phagocytosis and inflammatory cytokine release (TNF, IL-1β, IL-6). M1 polarization occurs via IFN-γ and LPS exposure, producing pro-inflammatory mediators and ROS. M2 polarization via IL-4/IL-13 promotes tissue repair through arginase-1, TGF-β, and IL-10 production. Macrophages also participate in efferocytosis (clearance of apoptotic cells) and resolution via SPM receptor expression.
Macrophage polarization determines whether inflammation resolves or becomes chronic. In cPNI practice, interventions must shift macrophages from persistent M1 activation (metainflammation) toward M2/resolution phenotypes through metabolic reprogramming, SPM supplementation, and addressing upstream drivers like gut dysbiosis and chronic stress.
- M1 macrophages produce TNF, IL-1β, IL-6, iNOS, and ROS
- M2 macrophages produce IL-10, TGF-β, arginase-1, and SPM receptors
- Tissue-resident macrophages include alveolar, Kupffer (liver), microglia (brain), and peritoneal macrophages
- Macrophages express dopamine receptors and respond to catecholamines
- Tumor-associated macrophages (TAMs) typically exhibit M2-like phenotype promoting angiogenesis
- Macrophages are key producers and targets of specialized pro-resolving mediators (SPMs)
- TNF — Primary pro-inflammatory cytokine produced by M1 macrophages
- IL-1β — Key inflammatory cytokine secreted following inflammasome activation
- IL-6 — Pleiotropic cytokine produced by macrophages driving acute phase response
- IL-10 — Anti-inflammatory cytokine produced by M2 macrophages
- TGF-beta — Immunosuppressive cytokine promoting tissue repair and fibrosis
- PAMPs — Pathogen patterns recognized by macrophage TLRs triggering activation
- DAMPs — Endogenous danger signals activating macrophage inflammatory programs
- TLR4 — Pattern recognition receptor detecting LPS and triggering M1 polarization
- LPS — Bacterial endotoxin activating macrophages via TLR4
- T cells — Interact bidirectionally - macrophages present antigens, T cells regulate polarization
- IFN-γ — Th1 cytokine driving M1 macrophage polarization
- dopamine — Neurotransmitter modulating macrophage function via dopamine receptors
- cortisol — Glucocorticoid that can suppress or enhance macrophage function depending on context
- SPMs — Specialized pro-resolving mediators promoting M2 polarization and efferocytosis
- Resolvins — Lipid mediators enhancing macrophage phagocytosis and resolution
- efferocytosis — Macrophage clearance of apoptotic cells essential for resolution
- NF-κB — Transcription factor activated in macrophages driving inflammatory gene expression
- HIF-1α — Transcription factor regulating macrophage metabolism and M1 polarization in hypoxia
- gut dysbiosis — Source of LPS driving chronic macrophage activation
- chronic low-grade inflammation — Sustained M1 macrophage activation underlying metainflammation
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