Bullous pemphigoid outcome is associated with CXCL10-induced matrix metalloproteinase 9 secretion from monocytes and neutrophils but not lymphocytes

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Bullous pemphigoid outcome is associated with CXCL10-induced matrix metalloproteinase 9 secretion from monocytes and neutrophils but not lymphocytes Meriem Riani, MSc, Sébastien Le Jan, PhD, Julie Plée, MD, Anne Durlach, MD, PhD, Richard Le Naour, PhD, Guy Haegeman, PhD, Philippe Bernard, MD, PhD, Frank Antonicelli, PhD Journal of Allergy and Clinical Immunology Volume 139, Issue 3, Pages 863-872.e3 (March 2017) DOI: 10.1016/j.jaci.2016.08.012 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 CXCL10 expression at skin lesional sites and in biological fluids of patients with BP. A, CXCL10 and CXCR3 immunohistochemistry on skin biopsy specimens of patients with BP. B, CXCL10 concentrations in serum of healthy subjects, serum of patients with BP, and blister fluid (BF) of patients with BP at baseline. C, Serum variations of CXCL10 concentrations between days 0 and 60 in patients with (R) and without (NR) relapse. D-F, CXCL10 gene expression in cytokine-stimulated lymphocytes and monocytes from patients with BP (Fig 1, D), serum- and BF-induced PBMCs from, healthy subjects (Fig 1, E), and cytokine-stimulated BP monocyte-derived macrophages (Fig 1, F). **P < .01 and ***P < .001. Journal of Allergy and Clinical Immunology 2017 139, 863-872.e3DOI: (10.1016/j.jaci.2016.08.012) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Distribution of IL-17 and CXCL10 expression in populations with BP. Venn diagram showing the number of patients expressing IL-17 and CXCL10 at diagnosis and after 2 months of treatment, respectively, in the global population with BP (A and B), patients with BP in remission (C and D), and those who experienced further relapsed (E and F). Journal of Allergy and Clinical Immunology 2017 139, 863-872.e3DOI: (10.1016/j.jaci.2016.08.012) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 MMP-9 secretion upon CXCL10 stimulation of inflammatory cells. A, MMP-9 activity measured by means of zymography in PMN cells and PBMCs from healthy control subjects or patients with BP and stimulated with CXCL10. B and C, Quantification of MMP-9 activity in PMN cells (Fig 3, B) and PBMCs (Fig 3, C). Error bars denote means ± SEMs, and 2-way ANOVA was used for statistics. *P < .05 and **P < .01. ns, Not significant. Journal of Allergy and Clinical Immunology 2017 139, 863-872.e3DOI: (10.1016/j.jaci.2016.08.012) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 CXCL10 selectively induced MMP-9 expression in monocytes from patients with BP. A, Gel zymography of MMP-9 activity in lymphocytes and monocytes from healthy control subjects and patients with BP upon CXCL10 stimulation. B and C, Quantification of MMP-9 activity in lymphocytes (Fig 4, B) and monocytes (Fig 4, C). D, CXCL10-induced MMP9 mRNA expression in monocytes from healthy control subjects and patients with BP. *P < .05. ns, Not significant. Journal of Allergy and Clinical Immunology 2017 139, 863-872.e3DOI: (10.1016/j.jaci.2016.08.012) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Expression of CXCR3A and CXCR3B isoforms in lymphocytes and monocytes. CXCR3A and CXCR3B mRNA expression in lymphocytes (A) and monocytes (B) isolated from control subjects and patients with BP. CTR, Control subjects. Journal of Allergy and Clinical Immunology 2017 139, 863-872.e3DOI: (10.1016/j.jaci.2016.08.012) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Signaling pathways involved in CXCL10-induced MMP-9 secretion. A, Western blotting analysis of signaling pathway activation in CXCL10-stimulated THP-1 cells. B, Effects of specific inhibitors for AKT (LY294002), ERK (U0126), p38 (SB203580), and NF-κB (SN50) on CXCL10-induced MMP-9 activity in THP-1 cells, monocytes, and PMN cells. C, Dose effects of methylprednisolone or compound A on CXCL10-induced MMP-9 activity in THP-1 cells. Journal of Allergy and Clinical Immunology 2017 139, 863-872.e3DOI: (10.1016/j.jaci.2016.08.012) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 CXCL10 expression in nonimmune resident cells at the lesion site in patients with BP. CXCL10, as analyzed by using immunohistochemistry (IHC), was expressed by keratinocytes (indicated by arrowheads in A) and fibroblasts and vascular cells (indicated by arrowheads and the arrow, respectively, in B) at the lesion site in skin biopsy specimens from patients with BP. Journal of Allergy and Clinical Immunology 2017 139, 863-872.e3DOI: (10.1016/j.jaci.2016.08.012) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Overexpression of both CXCR3A and CXCR3B increased MMP-9 activity in a monocytic cell line. A, CXCR3A and CXCR3B expression analyzed by using quantitative RT-PCR in a CXCR3A- or CXCR3B-transfected THP-1 cell line with respect to the empty vector-transfected THP-1 cells. B, MMP-9 activity measured by using zymography in CXCR3A- or CXCR3B-transfected THP-1 cells stimulated or not with CXCL10. Journal of Allergy and Clinical Immunology 2017 139, 863-872.e3DOI: (10.1016/j.jaci.2016.08.012) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions