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

Lopa M Das1, Julie Rosenjack1, Liemin Au1

  • 1Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.

The Journal of Investigative Dermatology
|September 4, 2014
PubMed

Insights

Rosiglitazone (Rosi) unexpectedly creates pro-inflammatory macrophages in IL-6 deficient conditions, worsening tissue damage. This effect, linked to chronic wounds, can be reversed by IL-6 or iNOS neutralization.

Area of Science:

  • Immunology
  • Wound Healing
  • Pharmacology

Background:

  • Macrophages are crucial for tissue repair after injury.
  • Excessive macrophage activity can lead to tissue damage and delayed wound healing.
  • Interleukin-6 (IL-6) plays a role in regulating macrophage function.

Purpose of the Study:

  • To investigate the paradoxical effect of rosiglitazone (Rosi) on macrophage activation in the context of IL-6 deficiency.
  • To elucidate the molecular mechanisms underlying Rosi-induced hyper-inflammation.
  • To identify potential therapeutic strategies for reversing Rosi-induced tissue damage.

Main Methods:

  • Utilized IL-6-deficient mice and wild-type mice with induced anti-IL-6 auto-antibodies.
  • Administered rosiglitazone (Rosi) to assess its impact on macrophage phenotype and function.
  • Analyzed the expression of key signaling molecules including suppressor of cytokine signaling 3 (SOCS3), signal transducer and activator of transcription 3 (STAT3), NF-κB, and inducible nitric oxide synthase (iNOS).
  • Evaluated the effects of recombinant IL-6, macrophage infiltration blockade, and iNOS neutralization in vivo.

Main Results:

  • Rosiglitazone (Rosi) paradoxically induced pro-inflammatory macrophages in IL-6 deficient settings.
  • Rosi upregulated SOCS3, altering the STAT3/NF-κB ratio, leading to hyper-induction of iNOS.
  • This macrophage activation resulted in de novo tissue destruction, mimicking chronic wounds.
  • Recombinant IL-6, blocking macrophage infiltration, or neutralizing iNOS reversed the observed tissue damage.

Conclusions:

  • Rosiglitazone exhibits an unanticipated role in promoting hyper-inflammatory macrophage activation under IL-6 deficient conditions.
  • The findings offer critical insights into the pathogenesis of chronic wounds associated with IL-6 deficiency.
  • Targeting iNOS or restoring IL-6 signaling may represent viable therapeutic approaches for managing such conditions.

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