CXCR2 ligands and G-CSF mediate PKCα-induced intraepidermal inflammation
Christophe Cataisson, … , Saveria Pastore, Stuart H. Yuspa
Christophe Cataisson, … , Saveria Pastore, Stuart H. Yuspa
Published October 2, 2006
Citation Information: J Clin Invest. 2006;116(10):2757-2766. https://doi.org/10.1172/JCI27514.
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Research Article Dermatology

CXCR2 ligands and G-CSF mediate PKCα-induced intraepidermal inflammation

Abstract

Transgenic mice overexpressing PKCα in the epidermis (K5-PKCα mice) exhibit an inducible severe intraepidermal neutrophilic inflammation and systemic neutrophilia when PKCα is activated by topical 12-O-tetradecanoylphorbol-13-acetate (TPA). This inducible model of cutaneous inflammation was used to define mediators of skin inflammation that may have clinical relevance. Activation of cutaneous PKCα increased the production of the chemotactic factors cytokine-induced neutrophil chemoattractant (KC) and macrophage inflammatory protein 2 (MIP-2) in murine plasma. TPA treatment of cultured K5-PKCα keratinocytes also released KC and MIP-2 into culture supernatants through an NF-κB–dependent pathway. MIP-2 and KC mediated the infiltration of neutrophils into the epidermis, since this was prevented by ablating CXCR2 in K5-PKCα mice or administering neutralizing antibodies against KC or MIP-2. The neutrophilia resulted from PKCα-mediated upregulation of cutaneous G-CSF released into the plasma independent of CXCR2. These responses could be inhibited by topical treatment with a PKCα-selective inhibitor. Inhibiting PKCα also reduced the basal and TNF-α– or TPA-induced expression of CXCL8 in cultured psoriatic keratinocytes, suggesting that PKCα activity may contribute to psoriatic inflammation. Thus, skin can be the source of circulating factors that have both local and systemic consequences, and these factors, their receptors, and possibly PKCα could be therapeutic targets for inhibition of cutaneous inflammation.

Authors

Christophe Cataisson, Andrea J. Pearson, Margaret Z. Tsien, Francesca Mascia, Ji-Liang Gao, Saveria Pastore, Stuart H. Yuspa

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Figure 4

Blocking CXCR2 ligands or CXCR2 deficiency prevents neutrophil infiltration in the skin of K5-PKCα mice.

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Blocking CXCR2 ligands or CXCR2 deficiency prevents neutrophil infiltrat...
A single dose of TPA (1 μg) in acetone was applied to the shaved backs of K5-PKCα mice that had been injected intravenously with either control IgG, KC-neutralizing antibodies, MIP-2–neutralizing antibodies, or a combination of KC- and MIP-2–neutralizing antibodies. Skin was collected 6 hours later, and MPO activity was determined (A). Blood was collected at sacrifice, and the number of peripheral blood neutrophils was determined from differential wbc counts (B). For A and B, bars represent the mean ± SEM for 4 animals, and results are representative of 4 experiments. *P < 0.05 versus IgG control group. (C) K5-PKCα mice expressing CXCR2 (K5-PKCα/CXCR2+/+), K5-PKCα mice heterozygous for CXCR2 (K5-PKCα/CXCR2+/–), and K5-PKCα mice deficient for CXCR2 (K5-PKCα/CXCR2–/–) were TPA painted; skin was collected 6 hours later, and sections were stained with H&E. White arrowheads show early stage of neutrophil infiltration into the hair follicles. MPO was determined in skin extracts from the mouse groups depicted in C (D) as well as peripheral blood neutrophil counts (E). For D and E, bars represent the mean ± SEM for 7 animals, and results are representative of 2 experiments. *P < 0.05 versus TPA-treated K5-PKCα/CXCR2+/+ group.