Surfactant proteins A and D suppress alveolar macrophage phagocytosis via interaction with SIRP alpha.
BACKGROUND
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 alpha (SIRP alpha).


OBJECTIVE
To investigate whether binding of SP-A and SP-D to SIRP alpha 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 alpha was confirmed in vitro using blocking antibodies and fibroblasts transfected with active and mutant SIRP alpha. 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.


RESULTS
Preincubation of macrophages with SP-A or SP-D suppressed apoptotic cell clearance. Surfactant suppression of macrophage phagocytosis was reversed by blocking SIRP alpha 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 alpha. During acute pulmonary inflammation, defects in apoptotic cell clearance are overcome by recruited mononuclear phagocytes.
Janssen
William J
WJ
Division of Pulmonary Medicine, Department of Medicine, National Jewish Medical and Research Center, K729, 1400 Jackson Street, Denver, CO 80206, USA. janssenw@njc.org
McPhillips
Kathleen A
KA
Dickinson
Matthew G
MG
Linderman
Derek J
DJ
Morimoto
Konosuke
K
Xiao
Yi Qun
YQ
Oldham
Kelly M
KM
Vandivier
R William
RW
Henson
Peter M
PM
Gardai
Shyra J
SJ
D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D001667:Binding, Competitive; D002478:Cells, Cultured; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology*; D008168:Lung / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010587:Phagocytosis / Q000276:immunology*; D037662:Pulmonary Surfactant-Associated Protein A / Q000276:immunology*; D037663:Pulmonary Surfactant-Associated Protein D / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology*
D000943:Antigens, Differentiation; D037662:Pulmonary Surfactant-Associated Protein A; D037663:Pulmonary Surfactant-Associated Protein D; D011971:Receptors, Immunologic; C501920:SIRPA protein, human