Hyper-inflammation and skin destruction mediated by rosiglitazone activation of macrophages in IL-6 deficiency

TY - JOUR

T1 - Hyper-inflammation and skin destruction mediated by rosiglitazone activation of macrophages in IL-6 deficiency

AU - Das, Lopa M

AU - Rosenjack, Julie

AU - Au, Liemin

AU - Galle, Pia Søndergaard

AU - Hansen, Morten Bagge

AU - Cathcart, Martha K

AU - McCormick, Thomas S

AU - Cooper, Kevin D

AU - Silverstein, Roy L

AU - Lu, Kurt Q

PY - 2015/2/13

Y1 - 2015/2/13

N2 - 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.

AB - 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.

KW - Animals

KW - Female

KW - Inflammation

KW - Interleukin-6

KW - Macrophage Activation

KW - Mice

KW - Mice, Inbred C3H

KW - Mice, Inbred C57BL

KW - NF-kappa B

KW - Nitric Oxide Synthase Type II

KW - STAT3 Transcription Factor

KW - Skin

KW - Thiazolidinediones

KW - Wound Healing

U2 - 10.1038/jid.2014.375

DO - 10.1038/jid.2014.375

M3 - Journal article

C2 - 25184961

SN - 0022-202X

VL - 135

SP - 389

EP - 399

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

IS - 2

ER -