| First Author | Das LM | Year | 2015 |
| Journal | J Invest Dermatol | Volume | 135 |
| Issue | 2 | Pages | 389-399 |
| PubMed ID | 25184961 | Mgi Jnum | J:217936 |
| Mgi Id | MGI:5616259 | Doi | 10.1038/jid.2014.375 |
| Citation | Das LM, et al. (2015) Hyper-inflammation and skin destruction mediated by rosiglitazone activation of macrophages in IL-6 deficiency. J Invest Dermatol 135(2):389-99 |
| abstractText | 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-gamma 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-kappaB 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. |
