SAA drives proinflammatory heterotypic macrophage differentiation in the lung via CSF-1R-dependent signaling.
Serum amyloid A (SAA) is expressed locally in chronic inflammatory conditions such as chronic obstructive pulmonary disease (COPD), where macrophages that do not accord with the classic M1/M2 paradigm also accumulate. In this study, the role of SAA in regulating macrophage differentiation was investigated in vitro using human blood monocytes from healthy subjects and patients with COPD and in vivo using an airway SAA challenge model in BALB/c mice. Differentiation of human monocytes with SAA stimulated the proinflammatory monokines IL-6 and IL-1β concurrently with the M2 markers CD163 and IL-10. Furthermore, SAA-differentiated macrophages stimulated with lipopolysaccharide (LPS) expressed markedly higher levels of IL-6 and IL-1β. The ALX/FPR2 antagonist WRW4 reduced IL-6 and IL-1β expression but did not significantly inhibit phagocytic and efferocytic activity. In vivo, SAA administration induced the development of a CD11c(high)CD11b(high) macrophage population that generated higher levels of IL-6, IL-1β, and G-CSF following ex vivo LPS challenge. Blocking CSF-1R signaling effectively reduced the number of CD11c(high)CD11b(high) macrophages by 71% and also markedly inhibited neutrophilic inflammation by 80%. In conclusion, our findings suggest that SAA can promote a distinct CD11c(high)CD11b(high) macrophage phenotype, and targeting this population may provide a novel approach to treating chronic inflammatory conditions associated with persistent SAA expression.
Department of Pharmacology and Therapeutics and.
Desiree
D
Anthony
Department of Pharmacology and Therapeutics and.
Jonathan L
JL
McQualter
Department of Pharmacology and Therapeutics and.
Maria
M
Bishara
Department of Pharmacology and Therapeutics and.
Ee X
EX
Lim
Department of Pharmacology and Therapeutics and.
Selcuk
S
Yatmaz
Department of Pharmacology and Therapeutics and.
Huei Jiunn
HJ
Seow
Department of Pharmacology and Therapeutics and.
Michelle
M
Hansen
Department of Respiratory Medicine, Royal Melbourne Hospital; Parkville, Victoria, Australia; and.
Michelle
M
Thompson
Department of Medicine, University of Melbourne, Parkville, Victoria, Australia;
John A
JA
Hamilton
Department of Respiratory Medicine, Royal Melbourne Hospital; Parkville, Victoria, Australia; and.
Louis B
LB
Irving
Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Bruce D
BD
Levy
Department of Pharmacology and Therapeutics and.
Ross
R
Vlahos
Department of Pharmacology and Therapeutics and.
Gary P
GP
Anderson
Department of Pharmacology and Therapeutics and bozis@unimelb.edu.au.
Steven
S
Bozinovski
D000818:Animals; D015153:Blotting, Western; D016022:Case-Control Studies; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D006410:Hematopoiesis; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000502:physiology; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000685:Serum Amyloid A Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D000685:Serum Amyloid A Protein; D016186:Receptor, Macrophage Colony-Stimulating Factor
ALX/FPR2 signaling; COPD; lung inflammation; macrophage biology