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Surfactant Proteins A and D Suppress Alveolar Macrophage Phagocytosis via Interaction with SIRP

¹ Division of Pulmonary Medicine, Department of Medicine, and ² Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado; and ³ Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to William J. Janssen, M.D., National Jewish Medical and Research Center, K729, 1400 Jackson Street, Denver, CO 80206. E-mail: janssenw{at}njc.org

Rationale: Efficient removal of apoptotic cells is essential for the resolution of acute pulmonary inflammation. Alveolar macrophages ingest apoptotic cells less avidly than other professional phagocytes at rest but overcome this defect during acute inflammation. Surfactant protein (SP)-A and SP-D are potent modulators of macrophage function and may suppress clearance of apoptotic cells through activation of the transmembrane receptor signal inhibitory regulatory protein (SIRP).

Objectives: To investigate whether binding of SP-A and SP-D to SIRP on alveolar macrophages suppresses apoptotic cell clearance.

Methods: Phagocytosis of apoptotic cells was assessed using macrophages pretreated with SP-A, SP-D, or the collectin-like molecule C1q. Binding of SP-A and SP-D to SIRP was confirmed in vitro using blocking antibodies and fibroblasts transfected with active and mutant SIRP. The effects of downstream molecules SHP-1 and RhoA on phagocytosis were studied using SHP-1–deficient mice, sodium stibogluconate, and a Rho kinase inhibitor. Lipopolysaccharide was given to chimeric mice to study the effects of SP-A and SP-D binding on inflammatory macrophages.

Measurements and Main Results: Preincubation of macrophages with SP-A or SP-D suppressed apoptotic cell clearance. Surfactant suppression of macrophage phagocytosis was reversed by blocking SIRP and inhibiting downstream molecules SHP-1 and RhoA. Macrophages from inflamed lungs ingested apoptotic cells more efficiently than resting alveolar macrophages. Recruited mononuclear phagocytes with low levels of SP-A and SP-D mediated this effect.

Conclusions: SP-A and SP-D tonically inhibit alveolar macrophage phagocytosis by binding SIRP. During acute pulmonary inflammation, defects in apoptotic cell clearance are overcome by recruited mononuclear phagocytes.

Key Words: macrophage • phagocytosis • cell surface molecules • inflammation • lung

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Apoptotic cell clearance is necessary for resolution of inflammation yet several studies show that resting alveolar macrophages ingest apoptotic cells poorly. Mechanisms to explain improved macrophage phagocytosis during inflammation are incomplete. What This Study Adds to the Field In the absence of inflammation, surfactant proteins A and D suppress alveolar macrophage phagocytosis. During acute inflammation, defects in apoptotic cell clearance are overcome by recruited mononuclear phagocytes.