Mechanisms of Inflammation: From Defense to Repair, and Chronicity

Introduction: What is Inflammation?

"Inflammation" is a biological defense response to infection or tissue injury, originally a process intended to restore tissue homeostasis. However, if this response becomes excessive or fails to resolve appropriately, it leads to chronic inflammation, causing tissue destruction and fibrosis, which underlies various diseases. Based on the latest findings reported in top journals like Cell and Nature, this article explains the molecular mechanisms of inflammation and the importance of how it "ends."

1. Initiation of Acute Inflammation: Sensing Danger Signals

Inflammation begins with the body sensing "danger signals."

• PAMPs (Pathogen-Associated Molecular Patterns): Components derived from bacteria or viruses (e.g., LPS).
• DAMPs (Damage-Associated Molecular Patterns): Self-components released from damaged cells (e.g., ATP, HMGB1).

These molecular patterns are recognized by receptors (e.g., TLRs) on immune cells like macrophages, activating signaling pathways such as NF-κB. As a result, pro-inflammatory cytokines like TNF-α and IL-6 are released, recruiting leukocytes such as neutrophils to the affected area (Biomedicines 2021).

2. Resolution of Inflammation: An Active Process

Previously, the resolution of inflammation was thought to be a "passive phenomenon that naturally disappears when the stimulus is gone." However, it is now clear that it is an "extremely active and strictly controlled program" (Nature 2014).

Role of Specialized Pro-resolving Mediators (SPMs)

At the peak of inflammation, lipid mediators called SPMs (Specialized Pro-resolving Mediators) are produced from omega-3 fatty acids (EPA/DHA).

• Resolvins
• Protectins
• Maresins

These stop neutrophil infiltration, promote phagocytosis by macrophages, and powerfully calm inflammation. Failure in SPM production is a key factor leading to the chronicity of inflammation.

Efferocytosis: Cleaning Up Dead Cells

Another key to inflammation resolution is Efferocytosis, where macrophages eat and process neutrophils that have finished their role and undergone apoptosis. Macrophages that have phagocytosed dead cells undergo reprogramming from "inflammatory (M1 type)" to "reparative (M2 type)," releasing anti-inflammatory cytokines (IL-10, TGF-β) to promote tissue repair (Nature Immunology 2010).

3. Transition to Chronic Inflammation: The Never-Ending Battle

If acute inflammation does not resolve properly, it becomes chronic.

• Persistent Stimuli: Pathogens or foreign bodies that cannot be fully removed.
• Failure of Resolution Mechanisms: Lack of SPMs or impaired Efferocytosis.

In chronic inflammation, macrophages and lymphocytes persist in the tissue, continuously attempting to destroy and rebuild it. Growth factors like TGF-β, produced excessively during this process, activate fibroblasts, causing irreversible "fibrosis."

Conclusion

Inflammation is a "double-edged sword." In drug discovery research, a new approach is gaining attention: not just stopping inflammation (Anti-inflammation), but promoting the resolution of inflammation (Pro-resolution). Our disease models capture this dynamic transition from inflammation to fibrosis, serving as powerful tools to explore the potential of novel therapeutics.

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References

1. Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510(7503):92-101.
2. Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454(7203):428-435.
3. Tabas I. Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol. 2010;10(1):36-46.