Macrophage Polarization (M1/M2): The "Accelerator" and "Brake" of Fibrosis

Introduction: The Duality of Macrophages

Macrophages are not just cells that eat pathogens. They possess "Plasticity," dramatically changing their properties according to the surrounding environment, and are commanders directing every phase of pathology from tissue destruction (inflammation) to repair (fibrosis) and healing (resolution of fibrosis). In fibrosis research, understanding macrophage Polarization, especially the balance between M1 and M2 types, is extremely important.

1. M1 Macrophages: The Initiators of Inflammation (Pro-inflammatory)

Activators

• LPS (Lipopolysaccharide): Bacterial component
• IFN-γ (Interferon-gamma): Th1 cell-derived cytokine

Main Roles

Appearing immediately after tissue injury, they trigger the inflammatory response.

• Release of Pro-inflammatory Cytokines: Massively produce TNF-α, IL-1β, IL-6, and IL-12, recruiting neutrophils and monocytes.
• Bactericidal Action: Produce Reactive Oxygen Species (ROS) and Nitric Oxide (NO) to eliminate pathogens.
• ECM Degradation: Produce MMPs (Matrix Metalloproteinases) and are involved in early tissue remodeling.

Relationship with Fibrosis

M1 types typically do not promote fibrosis, but chronic M1 activation causes persistent tissue damage, resulting in a trigger for fibrosis.

2. M2 Macrophages: The Promoters of Repair and Fibrosis (Pro-fibrotic)

Activators

• IL-4, IL-13: Th2 cell-derived cytokines

Main Roles

As inflammation heads towards resolution, macrophages change into M2 type and promote tissue repair.

• Anti-inflammatory Action: Produce IL-10 and TGF-β to calm inflammation.
• Tissue Repair: Secrete PDGF (Platelet-Derived Growth Factor) and IGF-1 (Insulin-like Growth Factor-1) to promote cell proliferation.
• Promotion of Fibrosis: This is the critical point. M2 macrophages are a major source of TGF-β, differentiating fibroblasts into myofibroblasts and powerfully inducing collagen production.

M2 Subtypes

M2 macrophages are further subdivided.

• M2a (Wound Healing Type): Induced by IL-4/IL-13. Produces high levels of TGF-β and PDGF, most powerfully promoting fibrosis.
• M2b (Regulatory Type): Induced by immune complexes. Involved in inflammation suppression and promotion of Th2 response.
• M2c (Deactivation/Repair Type): Induced by IL-10/Glucocorticoids. Involved in phagocytosis of dead cells (Efferocytosis) and tissue remodeling via MMP-9 production.

3. The "M1 to M2 Switch" in Fibrosis

Normal Healing Process

1. Immediately after Injury (M1 Dominant): Removal of pathogens and necrotic tissue by inflammation.
2. Repair Phase (M2 Dominant): Shift from M1 to M2, repairing and regenerating tissue.
3. Healing Complete: Upon completion of repair, M2 disappears, and tissue returns to normal.

Pathological Fibrosis Process

In fibrotic diseases, this switch mechanism is broken.

• Excessive/Persistent M2 Activation: Due to chronic injury or excessive Th2 cytokines, M2 macrophages persist.
• Never-Ending Repair: Because M2 continues to release excessive TGF-β, fibroblasts run wild, depositing more collagen than necessary and stiffening the organ.

4. "Resolution" of Fibrosis and Macrophages

Interestingly, it is also the role of macrophages to heal (resolve) fibrosis. In the recovery phase of fibrosis, Ly6C-low (Restorative) Macrophages appear and are known to secrete MMPs to degrade excessive collagen. In other words, macrophages are both "cells that create fibrosis" and "cells that dissolve fibrosis."

5. Macrophages as Therapeutic Targets

Strategies

1. Inhibition of M2 Polarization: Inhibiting IL-4/IL-13 signaling (JAK/STAT6 pathway) to suppress excessive M2 polarization.
2. Reprogramming to M1: Attempts to suppress fibrosis by returning M2 towards M1, similar to tumor immunity.
3. Depletion of Specific Subsets: Targeting and removing fibrosis-specific macrophages (e.g., SatM).

Conclusion

Control of macrophage polarization is one of the "main keeps" of fibrosis therapy. Precise control is required—not simply reducing macrophages, but suppressing "Bad M2 (Pro-fibrotic)" and utilizing "Good M2 (Repair/Resolution)." Our fibrosis models allow for quantitative evaluation of the M1/M2 balance within tissues using flow cytometry and immunostaining.

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References

1. Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016;44(3):450-462.
2. Murray PJ, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41(1):14-20.
3. Sica A, et al. Macrophage polarization in pathology. Cell Mol Life Sci. 2015;72(21):4111-4126.