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. 2010 Oct;130(10):2412-22.
doi: 10.1038/jid.2010.165. Epub 2010 Jun 17.

A subpopulation of CD163-positive macrophages is classically activated in psoriasis

Judilyn Fuentes-Duculan  1 , Mayte Suárez-Fariñas, Lisa C Zaba, Kristine E Nograles, Katherine C Pierson, Hiroshi Mitsui, Cara A Pensabene, Julia Kzhyshkowska, James G Krueger, Michelle A Lowes
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A subpopulation of CD163-positive macrophages is classically activated in psoriasis

Judilyn Fuentes-Duculan et al. J Invest Dermatol. 2010 Oct.

Abstract

Macrophages are important cells of the innate immune system, and their study is essential to gain greater understanding of the inflammatory nature of psoriasis. We used immunohistochemistry and double-label immunofluorescence to characterize CD163(+) macrophages in psoriasis. Dermal macrophages were increased in psoriasis compared with normal skin and were identified by CD163, RFD7, CD68, lysosomal-associated membrane protein 2 (LAMP2), stabilin-1, and macrophage receptor with collagenous structure (MARCO). CD163(+) macrophages expressed C-lectins CD206/macrophage mannose receptor and CD209/DC-SIGN, as well as costimulatory molecules CD86 and CD40. They did not express mature dendritic cell (DC) markers CD208/DC-lysosomal-associated membrane glycoprotein, CD205/DEC205, or CD83. Microarray analysis of in vitro-derived macrophages treated with IFN-γ showed that many of the genes upregulated in macrophages were found in psoriasis, including STAT1, CXCL9, Mx1, and HLA-DR. CD163(+) macrophages produced inflammatory molecules IL-23p19 and IL-12/23p40 as well as tumor necrosis factor (TNF) and inducible nitric oxide synthase (iNOS). These data show that CD163 is a superior marker of macrophages, and identifies a subpopulation of "classically activated" macrophages in psoriasis. We conclude that macrophages are likely to contribute to the pathogenic inflammation in psoriasis, a prototypical T helper 1 (Th1) and Th17 disease, by releasing key inflammatory products.

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Figures

Figure 1
Figure 1. Macrophage markers were more abundant in psoriasis lesional skin compared to normal skin
Representative immunohistochemistry staining and cell counts in normal and psoriasis skin of (a) CD163, (b) RFD7, (c) CD68, (d) LAMP2, (e) Stabilin and (f) MARCO, showing a significantly increased number of positive cells/per mm epidermis surface length in psoriasis compared to normal skin. Each dot represents a patient. Bar = 100 μm. **p<0.01; ***p<0.001.
Figure 2
Figure 2. CD163+ macrophages co-expressed other macrophage markers in psoriasis lesional skin
CD163+ cells almost completely co-expressed (a) FXIIIA and (b) RFD7. (c) The majority of CD68+ cells in the reticular dermis were CD163+. (d) More than half of LAMP2+ cells and (e) Stabilin+ cells co-expressed CD163. (f) Some MARCO+ cells also coexpressed CD163. In all immunofluorescence figures, single-stained controls are above the merged image, white line denotes dermo-epidermal junction, dermal collagen fibers gave green autofluorescence, and antibodies conjugated with a fluorochrome often gave background epidermal fluorescence. Bar =100 μm.
Figure 3
Figure 3. Genomic signature of in vitro “classically activated” (M1) macrophages was over-expressed in psoriasis
(a) Heatmap of cytokine treated in-vitro derived macrophages, compared to control (C) for each condition. This heatmap showed that macrophages treated with LPS+IFNγ, IFNγ, LPS, and TNF were clustered together, while IL-4-treated macrophages were more distant. (b) Venn Diagrams of “M1” and “M2” macrophages showing the number of upregulated genes (in red) and downregulated genes (in green) and their overlap in psoriasis lesional skin compared to IFN-γ and IL-4 treated macrophages respectively.
Figure 4
Figure 4. CD163+ macrophages expressed IFN-γ regulated genes
Many CD163+ macrophages co-expressed (a) STAT1, (b) CXCL9, (c) Mx1 and, (d) HLA-DR. Bar =100 μm.
Figure 5
Figure 5. Expression of cytokines in in vitro-derived macrophages and psoriasis by RT-PCR and immunofluorescence. (a)
RT-PCR analysis of mRNA expression of IL-23p19, IL-12/IL-23p40, IL-12p35 and CCL20 in cytokine treated (IFNγ, IL-4, TNF-α, LPS and LPS+IFN) in vitro macrophages (n=7) compared to control. mRNA expression normalized to human acidic ribosomal protein (HARP). * p<0.05, ***p<0.001. Some CD163+ macrophages co-expressed products of classically activated macrophages, (b) IL-23p19, (c) IL-12/IL-23p40, and inflammatory mediators (d) INOS and (e) TNF-α. Bar =100 μm.
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