The complement system acts as a crucial mediator of innate immunity and inflammation. Its inflammatory role is primarily mediated through the generation of bioactive peptide fragments known as anaphylatoxins, especially C3a and C5a. These molecules link pathogen recognition to vascular, cellular, and immune responses, while strict regulatory mechanisms protect host tissues from damage.
Role of Complement System in Inflammation
1. Generation of Pro-Inflammatory Mediators
Activation of the complement system through any pathway (classical, lectin, or alternative) leads to the cleavage of C3 and C5, producing:
- C3a โ moderate inflammatory mediator
- C5a โ the most potent anaphylatoxin and chemotactic factor
Among these, C5a plays the dominant role in initiating and amplifying inflammatory responses.
2. Increased Vascular Permeability and Vasodilation
C3a and C5a bind to receptors on mast cells and basophils, triggering degranulation.
This results in the release of histamine, which causes:
- Vasodilation โ redness and heat
- Retraction of endothelial cells โ increased vascular permeability
Outcome: Plasma leakage into tissues, leading to edema (swelling).
3. Leukocyte Chemotaxis (Cell Recruitment)
C5a functions as one of the strongest chemotactic agents in the immune system.
- It establishes a chemical gradient
- Directs neutrophils and monocytes from blood vessels to the site of infection
This ensures rapid accumulation of immune cells where they are needed most.
4. Leukocyte Activation and Adhesion
Binding of C5a to leukocyte receptors leads to:
- Activation of neutrophils and macrophages
- Enhanced phagocytosis
- Induction of respiratory burst (generation of reactive oxygen species)
C5a also increases the expression of adhesion molecules (integrins) on leukocytes, facilitating:
- Margination
- Diapedesis
- Migration into inflamed tissues
5. Amplification of the Inflammatory Response
Complement activation further amplifies inflammation by:
- Inducing the release of pro-inflammatory cytokines (IL-1, IL-6, TNF-ฮฑ)
- Formation of the Membrane Attack Complex (MAC), which lyses bacteria
The release of microbial debris and danger signals further strengthens the inflammatory cascade.
Regulation of the Complement System
To prevent host tissue damage, the complement system is tightly regulated by membrane-bound and soluble regulatory proteins.
1. Protection of Host Cells (Self-Recognition Mechanism)
Healthy host cells express surface-bound complement regulators that act as molecular โbrakes.โ
Key Proteins:
- DAF (CD55)
- MCP (CD46)
Mechanism:
These proteins accelerate the decay of C3 and C5 convertases, thereby preventing continued complement activation on self cells.
2. Inhibition of MAC Formation (Protective Shield)
To prevent complement-mediated lysis of host cells:
Key Protein:
- CD59 (Protectin)
Mechanism:
CD59 binds to assembling MAC components and blocks C9 polymerization, preventing pore formation in host cell membranes.
3. Silent Clearance of Apoptotic Cells
Complement proteins also contribute to tissue homeostasis by clearing dying cells without inducing inflammation.
Mechanism:
- C1q and C3b bind to apoptotic cells
- These โtagsโ promote recognition and phagocytosis by macrophages
Outcome:
Non-inflammatory removal of apoptotic cells, preventing release of toxic intracellular contents and autoimmunity.
Conclusion
The complement system plays a dual role as a powerful inflammatory amplifier and a highly regulated defense mechanism. Through anaphylatoxins like C3a and C5a, it orchestrates vascular changes, leukocyte recruitment, and microbial killing. Simultaneously, regulatory proteins such as DAF, MCP, and CD59 ensure that host tissues are protected, maintaining immune balance and tissue homeostasis.