G-CSF Receptor Blockade Ameliorates Arthritic Pain and Disease.
G-CSF or CSF-3, originally defined as a regulator of granulocyte lineage development via its cell surface receptor (G-CSFR), can play a role in inflammation, and hence in many pathologies, due to its effects on mature lineage populations. Given this, and because pain is an extremely important arthritis symptom, the efficacy of an anti-G-CSFR mAb for arthritic pain and disease was compared with that of a neutrophil-depleting mAb, anti-Ly6G, in both adaptive and innate immune-mediated murine models. Pain and disease were ameliorated in Ag-induced arthritis, zymosan-induced arthritis, and methylated BSA/IL-1 arthritis by both prophylactic and therapeutic anti-G-CSFR mAb treatment, whereas only prophylactic anti-Ly6G mAb treatment was effective. Efficacy for pain and disease correlated with reduced joint neutrophil numbers and, importantly, benefits were noted without necessarily the concomitant reduction in circulating neutrophils. Anti-G-CSFR mAb also suppressed zymosan-induced inflammatory pain. A new G-CSF-driven (methylated BSA/G-CSF) arthritis model was established enabling us to demonstrate that pain was blocked by a cyclooxygenase-2 inhibitor, suggesting an indirect effect on neurons. Correspondingly, dorsal root ganglion neurons cultured in G-CSF failed to respond to G-CSF in vitro, andCsf3rgene expression could not be detected in dorsal root ganglion neurons by single-cell RT-PCR. These data suggest that G-CSFR/G-CSF targeting may be a safe therapeutic strategy for arthritis and other inflammatory conditions, particularly those in which pain is important, as well as for inflammatory pain per se.
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria 3050, Australia.
Ming-Chin
0000-0002-6609-3524
MC
Lee
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria 3050, Australia.
James A
JA
McCubbin
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria 3050, Australia.
Anne D
AD
Christensen
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.|Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria 3010, Australia.
Daniel P
DP
Poole
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Pradeep
0000-0002-1983-7244
P
Rajasekhar
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
TinaMarie
T
Lieu
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.|Department of Surgery, Columbia University, New York, NY 10032.
Nigel W
NW
Bunnett
Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia.|South Australian Health and Medical Research Institute, Adelaide, South Australia 5000, Australia.|Visceral Pain Group, Department of Human Physiology, Flinders University, Bedford Park, South Australia 5042, Australia.
Sonia
S
Garcia-Caraballo
Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia.|South Australian Health and Medical Research Institute, Adelaide, South Australia 5000, Australia.|Visceral Pain Group, Department of Human Physiology, Flinders University, Bedford Park, South Australia 5042, Australia.
Andelain
0000-0001-8134-7919
A
Erickson
Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia.|South Australian Health and Medical Research Institute, Adelaide, South Australia 5000, Australia.|Visceral Pain Group, Department of Human Physiology, Flinders University, Bedford Park, South Australia 5042, Australia.
Stuart M
SM
Brierley
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria 3050, Australia.
Reem
0000-0002-8292-1895
R
Saleh
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria 3050, Australia.
Adrian
0000-0003-3640-2338
A
Achuthan
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria 3050, Australia.
Andrew J
AJ
Fleetwood
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia; and.|School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia.
Robin L
0000-0002-6841-7422
RL
Anderson
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria 3050, Australia; jahami@unimelb.edu.au.
John A
0000-0002-9493-9224
JA
Hamilton
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria 3050, Australia.
Andrew D
AD
Cook
D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use*; D000950:Antigens, Ly / Q000276:immunology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000628:therapy*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D047589:Leukocyte Reduction Procedures; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D059408:Pain Management; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D019138:Antibodies, Blocking; D000950:Antigens, Ly; C480309:Ly6G antigen, mouse; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor