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

Das LM, Rosenjack J, Au L, Galle PS, Hansen MB, Cathcart MK, McCormick TS, Cooper KD, Silverstein RL, Lu KQ - J. Invest. Dermatol. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.

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.

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Rosiglitazone (Rosi) treatment in the presence of auto-antibodies against IL-6 drives increased inducible nitric oxide synthase (iNOS) expression and delayed wound healing. Female C3HHeN mice were immunized with IL-6 analogs to induce aABIL-6 before experimentation. Age-matched C3HHeN mice with topical Rosi in the presence or absence of circulating aAB-IL-6 were subjected to the wounding protocol. (a) The exacerbation of wound formation and the rate of wound healing was monitored, (b) wound healing was quantitated as a percent of initial wound size n=3 mice, and (c) RNA was extracted from the skin of all three experimental groups at 24 hours post aABIL-6 treatment for analysis of iNOS mRNA expression. Values are means±SE. *P<0.05, n=4.
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fig5: Rosiglitazone (Rosi) treatment in the presence of auto-antibodies against IL-6 drives increased inducible nitric oxide synthase (iNOS) expression and delayed wound healing. Female C3HHeN mice were immunized with IL-6 analogs to induce aABIL-6 before experimentation. Age-matched C3HHeN mice with topical Rosi in the presence or absence of circulating aAB-IL-6 were subjected to the wounding protocol. (a) The exacerbation of wound formation and the rate of wound healing was monitored, (b) wound healing was quantitated as a percent of initial wound size n=3 mice, and (c) RNA was extracted from the skin of all three experimental groups at 24 hours post aABIL-6 treatment for analysis of iNOS mRNA expression. Values are means±SE. *P<0.05, n=4.

Mentions: Next, we sought to determine the effect of Rosi in states of physiologic IL-6 deficiency. We previously demonstrated that aAB-IL-6 is measurable in 10% of Danish blood donors with 0.1% of them producing high amounts of neutralizing aAB-IL-6 (Hansen et al., 1991; Galle et al., 2004; Fosgerau et al., 2010). To determine whether in vivo autoantibody-mediated deficiency of IL-6 combined with Rosi would drive hyper-inflammation and tissue destruction, we used a vaccination protocol based on murine IL-6 analogs that induces high titers of aAB-IL-6 (Ciapponi et al., 1997; Galle et al., 2007). Control (C3HEN) and aAB-IL-6 mice were then subjected to the previously described inflammatory wound protocol with topical Rosi. By day 3, wounds in aAB-IL-6 mice were enlarged with little contraction compared with controls. By day 9, the wounds of C3HEN mice had progressed toward resolution, whereas the wounds of the aAB-IL-6 mice remained enlarged (Figure 5a and b). Strikingly, wound closure was delayed by 5 days in these mice compared with controls (Figure 5b). At 24 hours, wound areas of aAB-IL-6 mice were 50% larger compared with initial wound size (Figure 5a and b), which corresponded to a significant increase in iNOS relative mRNA expression (Figure 5c) from skin biopsies obtained from the wound. Thus, iNOS induction of aAB-IL-6-induced mice is reminiscent of high iNOS levels in IL-6−/− mice subject to our treatment protocol (Figure 2a) and supports our hypothesis that the observed paradoxical hyper-inflammatory effect of Rosi is due to a deficiency in IL-6 and its signaling.


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

Das LM, Rosenjack J, Au L, Galle PS, Hansen MB, Cathcart MK, McCormick TS, Cooper KD, Silverstein RL, Lu KQ - J. Invest. Dermatol. (2014)

Rosiglitazone (Rosi) treatment in the presence of auto-antibodies against IL-6 drives increased inducible nitric oxide synthase (iNOS) expression and delayed wound healing. Female C3HHeN mice were immunized with IL-6 analogs to induce aABIL-6 before experimentation. Age-matched C3HHeN mice with topical Rosi in the presence or absence of circulating aAB-IL-6 were subjected to the wounding protocol. (a) The exacerbation of wound formation and the rate of wound healing was monitored, (b) wound healing was quantitated as a percent of initial wound size n=3 mice, and (c) RNA was extracted from the skin of all three experimental groups at 24 hours post aABIL-6 treatment for analysis of iNOS mRNA expression. Values are means±SE. *P<0.05, n=4.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4291681&req=5

fig5: Rosiglitazone (Rosi) treatment in the presence of auto-antibodies against IL-6 drives increased inducible nitric oxide synthase (iNOS) expression and delayed wound healing. Female C3HHeN mice were immunized with IL-6 analogs to induce aABIL-6 before experimentation. Age-matched C3HHeN mice with topical Rosi in the presence or absence of circulating aAB-IL-6 were subjected to the wounding protocol. (a) The exacerbation of wound formation and the rate of wound healing was monitored, (b) wound healing was quantitated as a percent of initial wound size n=3 mice, and (c) RNA was extracted from the skin of all three experimental groups at 24 hours post aABIL-6 treatment for analysis of iNOS mRNA expression. Values are means±SE. *P<0.05, n=4.
Mentions: Next, we sought to determine the effect of Rosi in states of physiologic IL-6 deficiency. We previously demonstrated that aAB-IL-6 is measurable in 10% of Danish blood donors with 0.1% of them producing high amounts of neutralizing aAB-IL-6 (Hansen et al., 1991; Galle et al., 2004; Fosgerau et al., 2010). To determine whether in vivo autoantibody-mediated deficiency of IL-6 combined with Rosi would drive hyper-inflammation and tissue destruction, we used a vaccination protocol based on murine IL-6 analogs that induces high titers of aAB-IL-6 (Ciapponi et al., 1997; Galle et al., 2007). Control (C3HEN) and aAB-IL-6 mice were then subjected to the previously described inflammatory wound protocol with topical Rosi. By day 3, wounds in aAB-IL-6 mice were enlarged with little contraction compared with controls. By day 9, the wounds of C3HEN mice had progressed toward resolution, whereas the wounds of the aAB-IL-6 mice remained enlarged (Figure 5a and b). Strikingly, wound closure was delayed by 5 days in these mice compared with controls (Figure 5b). At 24 hours, wound areas of aAB-IL-6 mice were 50% larger compared with initial wound size (Figure 5a and b), which corresponded to a significant increase in iNOS relative mRNA expression (Figure 5c) from skin biopsies obtained from the wound. Thus, iNOS induction of aAB-IL-6-induced mice is reminiscent of high iNOS levels in IL-6−/− mice subject to our treatment protocol (Figure 2a) and supports our hypothesis that the observed paradoxical hyper-inflammatory effect of Rosi is due to a deficiency in IL-6 and its signaling.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.

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.

Show MeSH
Related in: MedlinePlus