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Surfactant protein A regulates complement activation
W T Watford1, J R Wright, C G Hester
1Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Insights
Pulmonary surfactant protein A (SP-A) binds to C1q, inhibiting the formation of the classical complement pathway. This interaction suggests SP-A may regulate complement activation and inflammation in the lungs.
Area of Science:
- Immunology
- Pulmonary Medicine
- Biochemistry
Background:
- The classical complement pathway, initiated by the C1 complex, is crucial for pathogen clearance.
- C1 is a calcium-dependent complex comprising C1q, C1r, and C1s.
- Pulmonary surfactant protein A (SP-A) shares structural similarities with C1q.
Purpose of the Study:
- To investigate the functional significance of the interaction between SP-A and complement protein C1q.
- To determine if SP-A regulates the classical complement pathway.
Main Methods:
- Binding studies to assess SP-A interaction with C1q and intact C1.
- Assays to evaluate the effect of SP-A on C1 complex formation and immune complex binding.
- Functional assays using C1q-depleted serum to measure classical pathway activity.
Main Results:
- SP-A directly binds to C1q, but not effectively to intact C1.
- SP-A binding to C1q inhibits the association of C1q with C1r and C1s, preventing C1 complex formation.
- SP-A blocks C1q/C1 binding to immune complexes and prevents restoration of classical pathway activity in depleted serum.
Conclusions:
- SP-A down-regulates complement activity by interfering with C1 complex formation via C1q.
- SP-A may play a protective role in the lungs by limiting C1q-mediated complement activation and inflammation.
Abstract:
Complement proteins aid in the recognition and clearance of pathogens from the body. C1, the first protein of the classical pathway of complement activation, is a calcium-dependent complex of one molecule of C1q and two molecules each of C1r and C1s, the serine proteases that cleave complement proteins. Upon binding of C1q to Ag-bound IgG or IgM, C1r and C1s are sequentially activated and initiate the classical pathway of complement. Because of structural and functional similarities between C1q and members of the collectin family of proteins, including pulmonary surfactant protein A (SP-A), we hypothesized that SP-A may interact with and regulate proteins of the complement system. Previously, SP-A was shown to bind to C1q, but the functional significance of this interaction has not been investigated. Binding studies confirmed that SP-A binds directly to C1q, but only weakly to intact C1. Further investigation revealed that the binding of SP-A to C1q prevents the association of C1q with C1r and C1s, and therefore the formation of the active C1 complex required for classical pathway activation. This finding suggests that SP-A may share a common binding site for C1r and C1s or Clq. SP-A also prevented C1q and C1 from binding to immune complexes. Furthermore, SP-A blocked the ability of C1q to restore classical pathway activity to C1q-depleted serum. SP-A may down-regulate complement activity through its association with C1q. We hypothesize that SP-A may serve a protective role in the lung by preventing C1q-mediated complement activation and inflammation along the delicate alveolar epithelium.