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

Abstract

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 a (SIRPa). Objectives: To investigate whether binding of SP-A and SP-D to SIRPa 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 SIRPa was confirmed in vitro using blocking antibodies and fibroblasts transfected with active and mutant SIRPa. 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.

The transcriptome of nitrofen-induced pulmonary hypoplasia in the rat model of congenital diaphragmatic hernia

“…We report that rno-miR-3585-5p negatively alters two genes; BAZ2A and SIRPA; however, the exact mechanism is poorly understood. It has been shown that SIRPA, a member of the signalregulatory-protein family, can interact with surfactant proteins A and D to suppress alveolar phagocytosis without triggering an inflammatory response (41). This protein can be phosphorylated by tyrosine kinases and is found to participate in signal transduction triggered by CD47 and mediated by various growth factor receptors.…”

Signal regulatory protein alpha (SIRPα)/CD47 interaction and function

“…Further studies showed that SIRPα engagement through SP-A or SP-D lead to decreased uptake of apoptotic cells by alveolar cells. However during inflammation newly recruited macrophages escape this blocking and can then give efficient clearance of apoptotic cells [33]. This is an important concept as one is not be able to assume a receptor is available for ligand engagement just because of its presence.…”

Evolutionarily Conserved Paired Immunoglobulin-like Receptor α (PILRα) Domain Mediates Its Interaction with Diverse Sialylated Ligands

“…The presence of two sialylated glycopeptides was consistent with the LC-MS analysis of reduced hCD99-Fc. The detected sialoglycopeptide APDGGFLDLSDALPDNENKKPT 41 AIPK contained Thr-41 and a Ser residue that potentially could be O-glycosylated. However, the exact site of O-glycosylation could not have been sequenced through the performed type of LC-MS experiment.…”