Therapeutic targeting of the G-CSF receptor reduces neutrophil trafficking and joint inflammation in antibody-mediated inflammatory arthritis
- Author(s)
- Campbell, IK; Leong, D; Edwards, KM; Rayzman, V; Ng, M; Goldberg, GL; Wilson, NJ; Scalzo-Inguanti, K; Mackenzie-Kludas, C; Lawlor, KE; Wicks, IP; Brown, LE; Baz Morelli, A; Panousis, C; Wilson, MJ; Nash, AD; McKenzie, BS; Andrews, AE;
- Journal Title
- Journal of Immunology
- Publication Type
- Journal Article in press
- Abstract
- 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-1beta, 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.
- Publisher
- ASI
- Research Division(s)
- Inflammation
- PubMed ID
- 27807194
- Publisher's Version
- https://doi.org/10.4049/jimmunol.1600121
- NHMRC Grants
- NHMRC/1023407,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2016-11-14 11:36:20
Last Modified: 2016-11-17 11:33:54