Therapeutic Targeting of the G-CSF Receptor Reduces Neutrophil Trafficking and Joint Inflammation in Antibody-Mediated Inflammatory Arthritis.
G-CSF is a hemopoietic growth factor that has a role in steady state granulopoiesis, as well as in mature neutrophil activation and function. G-CSF- and G-CSF receptor-deficient mice are profoundly protected in several models of rheumatoid arthritis, and Ab blockade of G-CSF also protects against disease. To further investigate the actions of blocking G-CSF/G-CSF receptor signaling in inflammatory disease, and as a prelude to human studies of the same approach, we developed a neutralizing mAb to the murine G-CSF receptor, which potently antagonizes binding of murine G-CSF and thereby inhibits STAT3 phosphorylation and G-CSF receptor signaling. Anti-G-CSF receptor rapidly halted the progression of established disease in collagen Ab-induced arthritis in mice. Neutrophil accumulation in joints was inhibited, without rendering animals neutropenic, suggesting an effect of G-CSF receptor blockade on neutrophil homing to inflammatory sites. Consistent with this, neutrophils in the blood and arthritic joints of anti-G-CSF receptor-treated mice showed alterations in cell adhesion receptors, with reduced CXCR2 and increased CD62L expression. Furthermore, blocking neutrophil trafficking with anti-G-CSF receptor suppressed local production of proinflammatory cytokines (IL-1β, IL-6) and chemokines (KC, MCP-1) known to drive tissue damage. Differential gene expression analysis of joint neutrophils showed a switch away from an inflammatory phenotype following anti-G-CSF receptor therapy in collagen Ab-induced arthritis. Importantly, G-CSF receptor blockade did not adversely affect viral clearance during influenza infection in mice. To our knowledge, we describe for the first time the effect of G-CSF receptor blockade in a therapeutic model of inflammatory joint disease and provide support for pursuing this therapeutic approach in treating neutrophil-associated inflammatory diseases.
CSL Ltd., Bio21 Institute, Parkville, Victoria 3010, Australia; ian.campbell@csl.com.au.
Ian K
IK
Campbell
CSL Ltd., Bio21 Institute, Parkville, Victoria 3010, Australia.
David
D
Leong
CSL Ltd., Bio21 Institute, Parkville, Victoria 3010, Australia.
Kirsten M
KM
Edwards
CSL Ltd., Bio21 Institute, Parkville, Victoria 3010, Australia.
Veronika
0000-0001-9268-8305
V
Rayzman
CSL Ltd., Bio21 Institute, Parkville, Victoria 3010, Australia.
Milica
M
Ng
Reid Rheumatology Laboratory, Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; and.
Gabrielle L
GL
Goldberg
CSL Ltd., Bio21 Institute, Parkville, Victoria 3010, Australia.
Nicholas J
NJ
Wilson
CSL Ltd., Bio21 Institute, Parkville, Victoria 3010, Australia.
Karen
0000-0002-3945-3133
K
Scalzo-Inguanti
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria 3000, Australia.
Charley
C
Mackenzie-Kludas
Reid Rheumatology Laboratory, Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; and.
Kate E
0000-0003-0471-6842
KE
Lawlor
Reid Rheumatology Laboratory, Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; and.
Ian P
IP
Wicks
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria 3000, Australia.
Lorena E
LE
Brown
CSL Ltd., Bio21 Institute, Parkville, Victoria 3010, Australia.
Adriana
A
Baz Morelli
CSL Ltd., Bio21 Institute, Parkville, Victoria 3010, Australia.
Con
C
Panousis
CSL Ltd., Bio21 Institute, Parkville, Victoria 3010, Australia.
Michael J
MJ
Wilson
CSL Ltd., Bio21 Institute, Parkville, Victoria 3010, Australia.
Andrew D
AD
Nash
CSL Ltd., Bio21 Institute, Parkville, Victoria 3010, Australia.
Brent S
BS
McKenzie
CSL Ltd., Bio21 Institute, Parkville, Victoria 3010, Australia.
Arna E
0000-0002-3324-8972
AE
Andrews
D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D007596:Joints / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology
D057134:Antibodies, Neutralizing; D016207:Cytokines; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor