Beyond polarization: a receptor-centered framework for macrophage function and therapy in skin diseases

Area of Science:

• Immunology
• Dermatology
• Cell Biology

Background:

• The M1/M2 macrophage polarization model is insufficient to explain macrophage functional diversity in skin diseases.
• Macrophages play critical roles in regulating cutaneous immunity and are implicated in various skin pathologies.

Purpose of the Study:

• To present a receptor-centered view of macrophage function in skin diseases.
• To introduce a modular "receptor-pathway-effector" framework for understanding macrophage heterogeneity.
• To explore how specific receptor modules contribute to macrophage roles in diverse skin conditions.

Main Methods:

• Narrative review of selected skin diseases.
• Analysis of macrophage function through a receptor-centered lens.
• Summarization of key macrophage receptor modules and their associated pathways.

Main Results:

• Macrophage receptors act as upstream sensors translating various signals into distinct functional programs (inflammatory, reparative, fibrotic, immunosuppressive).
• Representative receptor modules (e.g., pattern-recognition, cytokine, Fc, scavenger, checkpoint receptors) are summarized.
• This framework explains macrophage involvement in inflammation, remodeling, host defense, impaired repair, and tumor immune escape across multiple skin diseases.

Conclusions:

• A receptor-centered perspective complements existing models of macrophage heterogeneity.
• The proposed framework provides a clearer link between receptor signaling and disease-specific macrophage functions.
• Understanding these receptor-mediated mechanisms can inform biomarker discovery and therapeutic strategies for skin diseases.