Activated macrophages are essential in a murine model for T cell–mediated chronic psoriasiform skin inflammation
Honglin Wang, … , Ingo Haase, Karin Scharffetter-Kochanek
Honglin Wang, … , Ingo Haase, Karin Scharffetter-Kochanek
Published August 1, 2006
Citation Information: J Clin Invest. 2006;116(8):2105-2114. https://doi.org/10.1172/JCI27180.
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Research Article Dermatology

Activated macrophages are essential in a murine model for T cell–mediated chronic psoriasiform skin inflammation

Abstract

The CD18 hypomorphic (CD18hypo) PL/J mouse model clinically resembling human psoriasis is characterized by reduced expression of the common chain of β2 integrins (CD11/CD18) to only 2–16% of WT levels. Previously we found that this chronic psoriasiform skin inflammation also depends on the presence of CD4+ T cells. Herein we investigated the role of macrophages in this CD18hypo mouse model. Activated macrophages were significantly increased in lesional skin as well as in inflamed skin draining lymph nodes (DLNs) of affected CD18hypo mice and were identified as being an important source of TNF-α in vivo. Both depletion of macrophages and neutralization of TNF-α resulted in a significant alleviation of psoriasiform skin inflammation. As monocyte chemotactic protein 1 was enhanced in lesional skin of affected CD18hypo mice, we intradermally injected recombinant murine monocyte chemotactic protein-1 (rJE/MCP-1) alone or in combination with rTNF-α into the skin of healthy CD18hypo mice. Only simultaneous injection of rJE/MCP-1 and rTNF-α, but neither substance alone, resulted in the induction of psoriasiform skin inflammation around the injection sites with recruitment and activation of macrophages. Collectively, our data suggest that maintenance of psoriasiform skin inflammation critically depends on efficient recruitment and activation of macrophages with sufficient release of TNF-α.

Authors

Honglin Wang, Thorsten Peters, Daniel Kess, Anca Sindrilaru, Tsvetelina Oreshkova, Nico Van Rooijen, Athanasios Stratis, Andreas C. Renkl, Cord Sunderkötter, Meinhard Wlaschek, Ingo Haase, Karin Scharffetter-Kochanek

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Figure 6

The injection of a combination of rJE/MCP-1 and rTNF-α induces psoriasiform inflammatory skin lesions inCD18hypo PL/J mice.

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The injection of a combination of rJE/MCP-1 and rTNF-...
Neither injection of rJE/MCP-1 nor rTNF-α alone resulted in psoriasiform skin disease (Supplemental Figure 3 and data not shown). (A and B) A combination of 0.2 μg murine rJE/MCP-1 and 5,000 U rTNF-α, injected in 200 μl PBS intradermally in the upper back skin of nonaffected CD18hypo PL/J mice (A), led to the appearance of erythematous plaques covered with scales and crusts starting at day 4 after administration (B). (C and D) Skin samples from paraffin sections were stained with H&E before (C) and 10 days after treatment, when epidermal hyperplasia and an abundant inflammatory infiltrate were observed within the dermis (D). (E and F) Cryosections from skin samples before (E) and after treatment stained for the keratinocyte marker K14–Alexa 488 (green) showed an increase in epidermal thickness and enhanced expression of the K14 proliferation-associated marker 10 days after treatment (F). (G and H) At this same time point, a dermal inflammatory infiltrate predominantly consisting of F4/80–Alexa 488+– (green) and TNF-α–PE+–activated (red) macrophages (overlay, yellow) was identified (H) compared with day 0 (G). (I and J) Interestingly, virtually no CD4-FITC+ T cells (green) were present in the dermis before (I) or after treatment with rMCP-1 and rTNF-α (J). Cell nuclei were counterstained with DAPI (blue). Dotted lines indicate the border between epidermis and dermis. Original magnification, ×20.