Macrophages and neutrophils are the targets for immune suppression by glucocorticoids in contact allergy
Jan P. Tuckermann, … , Wolfgang Schmid, Günther Schütz
Jan P. Tuckermann, … , Wolfgang Schmid, Günther Schütz
Published May 1, 2007
Citation Information: J Clin Invest. 2007;117(5):1381-1390. https://doi.org/10.1172/JCI28034.
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Macrophages and neutrophils are the targets for immune suppression by glucocorticoids in contact allergy

Abstract

Glucocorticoids (GCs) are widely used in the treatment of allergic skin conditions despite having numerous side effects. Here we use Cre/loxP-engineered tissue- and cell-specific and function-selective GC receptor (GR) mutant mice to identify responsive cell types and molecular mechanisms underlying the antiinflammatory activity of GCs in contact hypersensitivity (CHS). CHS was repressed by GCs only at the challenge phase, i.e., during reexposure to the hapten. Inactivation of the GR gene in keratinocytes or T cells of mutant mice did not attenuate the effects of GCs, but its ablation in macrophages and neutrophils abolished downregulation of the inflammatory response. Moreover, mice expressing a DNA binding–defective GR were also resistant to GC treatment. The persistent infiltration of macrophages and neutrophils in these mice is explained by an impaired repression of inflammatory cytokines and chemokines such as IL-1β, monocyte chemoattractant protein-1, macrophage inflammatory protein-2, and IFN-γ–inducible protein 10. In contrast TNF-α repression remained intact. Consequently, injection of recombinant proteins of these cytokines and chemokines partially reversed suppression of CHS by GCs. These studies provide evidence that in contact allergy, therapeutic action of corticosteroids is in macrophages and neutrophils and that dimerization GR is required.

Authors

Jan P. Tuckermann, Anna Kleiman, Richard Moriggl, Rainer Spanbroek, Anita Neumann, Anett Illing, Björn E. Clausen, Brenda Stride, Irmgard Förster, Andreas J.R. Habenicht, Holger M. Reichardt, François Tronche, Wolfgang Schmid, Günther Schütz

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Figure 1

Dexamethasone treatment suppresses CHS but is ineffective when applied during the sensitization phase.

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Dexamethasone treatment suppresses CHS but is ineffective when applied d...
(A) Beginning at day –1 and continuing for 7 days, mice were treated with either PBS (rows 1 and 2) or dexamethasone (Dex; row 3). On day 0, mice were treated on the shaved back skin either with vehicle (row 1) or with DNFB (rows 2 and 3). All mice were challenged with DNFB at the ear on day 5, the effect of which was determined 24 hours later. *P < 0.01 (n = 6). (B and C) Wild-type mice were injected i.p. with either dexamethasone or vehicle. Twenty-four hours later, they were topically treated on the shaved back skin with the fluorophore FITC. After 18 hours, cells from regional lymph nodes were analyzed by flow cytometry. (B) FACS analysis of lymph node cells was performed to determine the level of expression of CD11c and loading with FITC. (C) Numbers of FITC-positive cells after treatment with either FITC alone or FITC in combination with dexamethasone. *P < 0.01. (D) Mice were treated as described in A except that the dexamethasone treatment was terminated at day 1 after DNFB sensitization (Dex 48 h; row 3) (n = 6).