Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic, Th17-derived cytokine thought to critically contribute to the pathogenesis of diverse autoimmune diseases, including rheumatoid arthritis and psoriasis. Treatment with monoclonal antibodies that block GM-CSF activity is associated with favorable therapeutic effects in patients with rheumatoid arthritis. We evaluated the role of GM-CSF as a potential target for therapeutic interference in psoriasis using a combined pharmacologic and genetic approach and the mouse model of imiquimod-induced psoriasiform dermatitis (IMQPD). Neutralization of murine GM-CSF by an anti-GM-CSF antibody ameliorated IMQPD. In contrast, genetic deficiency in GM-CSF did not alter the course of IMQPD, suggesting the existence of mechanisms compensating for chronic, but not acute, absence of GM-CSF. Further investigation uncovered an alternative pathogenic pathway for IMQPD in the absence of GM-CSF characterized by an expanded plasmacytoid dendritic cell population and release of IFNα and IL-22. This pathway was not activated in wild-type mice during short-term anti-GM-CSF treatment. Our investigations support the potential value of GM-CSF as a therapeutic target in psoriatic disease. The discovery of an alternative pathogenic pathway for psoriasiform dermatitis in the permanent absence of GM-CSF, however, suggests the need for monitoring during therapeutic use of long-term GM-CSF blockade.
| Original language | English |
|---|---|
| Article number | e0182646 |
| Journal | PLoS ONE |
| Volume | 12 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 08.2017 |
Funding
This research was supported by the research funding program Landes-Offensive zur Entwicklung Wissenschaftlich-?konomischer Exzellenz (LOEWE) of the Federal State of Hesse, Research Center for Translational Medicine and Pharmacology TMP to Prof. Burkhardt; the Else Kr?ner-Fresenius Foundation (EKFS), Research Training Group Translational Research Innovation ?Pharma (TRIP) to Dr. Scholz; the Federal Ministry of Education and Research of Germany (Arthromark TP4; 01 EC1401C) to Prof. Burkhardt; the Deutsche Forschungsgemeinschaft (Sa1960/5-1) and the Galderma F?rderkreis e.V. (Theodar-Nasemann-Award 2014) to Dr. Sadik; and the Fraunhofer Institute IME, Frankfurt am Main, Germany (editorial services). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Dr. Stefan Steidl (Morphosys AG) for the kind gift of the recombinant anti-GM-CSF antibody, MOR012507, and Sharon L. Cross, PhD, for editorial services.
Research Areas and Centers
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)
