Identification of TNF-related apoptosis-inducing ligand and other molecules that distinguish inflammatory from resident dendritic cells in patients with.

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Identification of TNF-related apoptosis-inducing ligand and other molecules that distinguish inflammatory from resident dendritic cells in patients with psoriasis Lisa C. Zaba, MD, PhD, Judilyn Fuentes-Duculan, MD, Narat John Eungdamrong, PhD, Leanne M. Johnson-Huang, PhD, Kristine E. Nograles, MD, Traci R. White, BS, Katherine C. Pierson, BA, Tim Lentini, BA, Mayte Suárez-Fariñas, PhD, Michelle A. Lowes, MBBS, PhD, James G. Krueger, MD, PhD Journal of Allergy and Clinical Immunology Volume 125, Issue 6, Pages 1261-1268.e9 (June 2010) DOI: 10.1016/j.jaci.2010.03.018 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Transcriptome of CD1c− DCs versus resident CD1c+ DCs from psoriatic dermis. A, Gating strategy used for cell sorting. HLA-DR+CD11c+CD163− myeloid DCs were sorted into CD1c− (red gate) and CD1c+ (blue gate) populations. B, Selected upregulated and downregulated inflammatory molecules from the transcriptome of CD1c− DC populations. The full list of differentially expressed genes can be found in Table E2. Journal of Allergy and Clinical Immunology 2010 125, 1261-1268.e9DOI: (10.1016/j.jaci.2010.03.018) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 RT-PCR of genes differentially upregulated in CD1c− DCs in nonlesional and lesional psoriatic skin. TLR2, TRAIL, S100A12, and CD32 were upregulated in lesional psoriatic skin (n = 11). Error bars indicate standard errors of the mean. ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2010 125, 1261-1268.e9DOI: (10.1016/j.jaci.2010.03.018) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Flow cytometric analysis of psoriatic dermal single-cell suspensions. A, CD1c− DCs (bottom row) express higher levels of TRAIL, TLR1, TLR2, CD68, CD14, and CD209 compared with CD1c+ DCs (top row). B, CD1c+ DCs express comparatively higher levels of the DC maturation antigens HLA-DR, CD86, CD83, and CD40. The red histogram represents antigen expression gated on HLA-DR+CD11c+CD163−CD1c+/− DCs, and the blue histogram is the isotype. Journal of Allergy and Clinical Immunology 2010 125, 1261-1268.e9DOI: (10.1016/j.jaci.2010.03.018) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Lesional CD11c+CD1c− DCs expressed TRAIL, and keratinocytes expressed TRAIL receptors. A, TRAIL antigen was present in lesional dermis. B, The majority of lesional CD11c+ cells expressed TRAIL, whereas few cells coexpressed TRAIL and CD1c. C-E, Many TRAIL+ cells expressed CD45 (Fig 4, C) and HLA-DR (Fig 4, D), and some T cells expressed TRAIL (Fig 4, E). F, There was no expression of DR5 but abundant DR4 and some expression of DcR2. Bar = 100 μm. Journal of Allergy and Clinical Immunology 2010 125, 1261-1268.e9DOI: (10.1016/j.jaci.2010.03.018) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Expression of the TH17-polarizing cytokines IL-23p40 and IL-12/IL-23p19 in cutaneous DCs in patients with psoriasis. A, CD1c+ resident DCs did not express IL-12/23p40 but did express IL-23p19. B, Inflammatory myeloid DCs (CD11c+) expressed both IL-23 subunits. C and D, TRAIL+ cells coexpressed some IL-12/IL-23p40 and IL-23p19, as well as iNOS and TNF. Bar = 100 μm. Journal of Allergy and Clinical Immunology 2010 125, 1261-1268.e9DOI: (10.1016/j.jaci.2010.03.018) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

CD1c− DCs were most similar to CD1c+ DCs and iDCs CD1c− DCs were most similar to CD1c+ DCs and iDCs. There was a clear (right-to-left) progression in the principal component (PC) analysis from macrophages (blue diamonds) and iDCs (green crosses) to psoriatic CD1c− DCs (red triangles), psoriatic CD1c+ DCs (black circles), and mature DCs (blue crosses). Monocytes were located far away from this “line” (pink triangles). Journal of Allergy and Clinical Immunology 2010 125, 1261-1268.e9DOI: (10.1016/j.jaci.2010.03.018) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Lesional CD11c+CD1c− DCs expressed TLR1, TLR2, S100A12, and CD32 Lesional CD11c+CD1c− DCs expressed TLR1, TLR2, S100A12, and CD32. A and B, TLR1 (Fig E2, A) and TLR2 (Fig E2, B) were coexpressed by most CD11c+ cells but not by CD1c+ cells. C, Many S100A12+ cells expressed CD11c, but very few coexpressed CD1c. D, CD32 was expressed by papillary dermal cells and was expressed by most CD11c+ and few CD1c+ cells. Bar = 100 μm. Journal of Allergy and Clinical Immunology 2010 125, 1261-1268.e9DOI: (10.1016/j.jaci.2010.03.018) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Expression of TRAIL on lesional macrophages Expression of TRAIL on lesional macrophages. Only occasional CD163+ macrophages expressed TRAIL. Bar = 100 μm. Journal of Allergy and Clinical Immunology 2010 125, 1261-1268.e9DOI: (10.1016/j.jaci.2010.03.018) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

The TRAIL receptor DR4 was expressed on lesional keratinocytes and blood vessels. A-C, DR4 was expressed on CD11c+ cells (Fig E4, A) but not on CD3+ T cells (Fig E4, B) or CD163+ macrophages (Fig E4, C). D-F, DR4 colocalized with the blood vessel antigens vimentin (Fig E4, D) and CD31 (Fig E4, E) and the growth receptor insulin-like growth factor 1 receptor b (IGFR1) (Fig E4, F). Bar = 100 μm. Journal of Allergy and Clinical Immunology 2010 125, 1261-1268.e9DOI: (10.1016/j.jaci.2010.03.018) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

TRAIL induced CCL20 in cultured human keratinocytes TRAIL induced CCL20 in cultured human keratinocytes. rh-TRAIL or TNF (in nanograms per milliliter) was cultured with pooled human keratinocytes (n = 3) for 24 hours, and normalized CCL20 mRNA (A) and protein (B) expression were measured. CCL20 protein was expressed as change from control value. ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2010 125, 1261-1268.e9DOI: (10.1016/j.jaci.2010.03.018) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Hypothesis for the role of TRAIL-expressing inflammatory DCs in psoriasis pathogenesis. TRAIL has downstream effects on keratinocytes (CCL20 induction and resultant leukocyte chemotaxis), vascular smooth muscle cells (insulin-like growth factor 1 receptor b induction and subsequent vascular smooth muscle cell proliferation), and endothelial cells (intercellular adhesion molecule 1 [ICAM-1] and E-selectin induction and leukocyte transmigration). CD1c−TRAIL+ inflammatory DCs also express receptors (TLR1/2 and CD32) and inflammatory molecules (S100A12 and IL-23) that potentiate innate and adaptive immunity. Journal of Allergy and Clinical Immunology 2010 125, 1261-1268.e9DOI: (10.1016/j.jaci.2010.03.018) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions