Abstract
Injury initiates recruitment of macrophages to support tissue repair; however, excessive macrophage activity may exacerbate tissue damage causing further destruction and subsequent delay in wound repair. Here we show that the peroxisome proliferation-activated receptor-γ agonist, rosiglitazone (Rosi), a medication recently reintroduced as a drug to treat diabetes and with known anti-inflammatory properties, paradoxically generates pro-inflammatory macrophages. This is observed in both IL-6-deficient mice and control wild-type mice experimentally induced to produce high titers of auto-antibodies against IL-6, mimicking IL-6 deficiency in human diseases. IL-6 deficiency when combined with Rosi-mediated upregulation of suppressor of cytokine signaling 3 leads to an altered ratio of nuclear signal transducer and activator of transcription 3/NF-κB that allows hyper-induction of inducible nitric oxide synthase (iNOS). Macrophages activated in this manner cause de novo tissue destruction, recapitulating human chronic wounds, and can be reversed in vivo by recombinant IL-6, blocking macrophage infiltration, or neutralizing iNOS. This study provides insight into an unanticipated paradoxical role of Rosi in mediating hyper-inflammatory macrophage activation significant for diseases associated with IL-6 deficiency.
| Original language | English |
|---|---|
| Journal | Journal of Investigative Dermatology |
| Volume | 135 |
| Issue number | 2 |
| Pages (from-to) | 389-99 |
| Number of pages | 11 |
| ISSN | 0022-202X |
| DOIs | |
| Publication status | Published - 13 Feb 2015 |
Keywords
- Animals
- Female
- Inflammation
- Interleukin-6
- Macrophage Activation
- Mice
- Mice, Inbred C3H
- Mice, Inbred C57BL
- NF-kappa B
- Nitric Oxide Synthase Type II
- STAT3 Transcription Factor
- Skin
- Thiazolidinediones
- Wound Healing
