Étude de la coopération entre les cellules dendritiques et les lymphocytes T dans les allergies aux produits chimiques FPH42

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Étude de la coopération entre les cellules dendritiques et les lymphocytes T dans les allergies aux produits chimiques FPH42 Dr Diane Antonios-Gholam PharmD, PhD Laboratoire de Toxicologie Clinique et Expérimentale Faculté de Pharmacie

Chemical allergy: major public health concern Chemical allergy 15-2 % of the general population suffer from allergic contact dermatitis. Peiser et al. Cell Mol Life Sci, 212 Major cause of occupational skin disease estimated newly reported annual incident of.5-1.9 in Europe. Kaplan et al. Nat Rev Immunol, 212 Nickel is the most frequent contact allergen (18.1%) followed by cobalt (5.9%) and chromium (3%) as diagnosed by patch testing. In Europe, an estimated 65 million people may be allergic to nickel. Uter et al. J. Eur. Acad. Dermatol. Venereol, 217 Diepgen et al. Contact dermatitis, 213

Chemical allergy: major public health concern T-cell mediated reactions (Gell-Coombs Type IV) Varying degrees of erythema, edema and vesiculation ACD caused by nickel / cobalt ACD caused by chromium

Drug and chemical allergy: complex mechanism Danger signals Second exposure T-cell mediated reactions Maculopapular exanthema induced by b-lactams Pustulosis exanthema Allergic contact dermatitis

Dendritic cells and T-cells interaction Th1 T-cell polarization IFN- Danger signals IL-12p7 IL-23 Th17 IL-17 IL-12p7 IL-23 p35 p4 p19 p4

Dendritic cells and T-cells interaction IL-12p7 IL-12p7 Ni 2+ IFN- IL-23 p35 p4 p38 MAPK NF-kB JAK/STAT-1 IRF-1 p19 p4 TH1 IL-12p4 IL-12p35 Th17 IFN- IL-17A Antonios et al., J Immunol. 21

Part. I Background Nickel-specific Th1 and Th17 cells were found in the blood and skin of nickel allergic patients. Peiser, Clin Dev Immunol, 213 Dyring-Andersen B et al. Contact dermatitis, 213 Pennino et al. J immunol, 21 Larsen et al. J Allergy Clin Immunol, 29 IL-17 amplifies allergic contact dermatitis: ACD clinical score correlated with the epidermal accumulation of IL-17A- producing T-cells. Schmidt et al. Contact dermatitis, 217 Pennino et al. J immunol, 21 Intraepidermal CD3+ IL-17+ cells, mostly distributed at the site of epidermal spongiosis and microvesiculation IL-17 deficient mice demonstrated strongly reduced ear swelling response (CHS) to contact allergens Nakae et al. Immunity, 22 He et al. J Immunol, 26 Induction of chemokines (CXCL-8, CXCL1) and cytokines (IL-6, IL-1) release from keratinocytes Peiser, Clin Dev Immunol, 213 Intensification of the ICAM-1 dependent keratinocyte-t cell interaction promoting nonspecific T cell-induced keratinocyte apoptosis. Pennino et al. J immunol, 21 Nakae et al. Immunity, 22 What are the mechanisms behind nickel-induced Th17 cells development?

Part. I Generation of human monocyte-derived dendritic cells (MoDC) Ficoll gradient Magnetic positive selection Culture for 5 days Day 5 Buffy coats Peripheral blood mononucleated cell Monocytes CD14+ Culture media + GM-CSF and IL-4 Immature dendritic cells (idc)

(pg/ml) (pg/ml) (pg/ml) Ni 2+ induces the production of IL-23, IL-12p4 and IL-12p7 by human MoDC IL-23 p19 p4 IL-12p7 p35 p4 A 15 1 5 ELISA-24hrs ( 5 µm; NiCl 2 5 µm; CoCl 2 5 µm; K 2 Cr 2 O 7 5 µm; LPS 25 ng/ml) IL-23 IL-12p4 IL-12p7 NiCl 2 CoCl 2 K 2 Cr 2 O 7 LPS 8 7 6 5 4 15 1 5 NiCl 2 CoCl 2 K 2 Cr 2 O 7 LPS 6 5 4 3 5 4 3 2 1 NiCl 2 CoCl 2 K 2 Cr 2 O 7 LPS N=4; p.5, Mann-Whitney Bechara R. et al. J Invest Dermatol. 217

(pg/ml) (pg/ml) (pg/ml) art. I Article 1 Ni 2+ induces the production of IL-23, IL-12p4 and IL-12p7 by human MoDC IL-23 p19 p4 IL-12p7 p35 p4 A 15 1 5 ELISA-24hrs ( 5 µm; NiCl 2 5 µm; CoCl 2 5 µm; K 2 Cr 2 O 7 5 µm; LPS 25 ng/ml) IL-23 IL-12p4 IL-12p7 NiCl 2 CoCl 2 K 2 Cr 2 O 7 LPS 8 7 6 5 4 15 1 5 NiCl 2 CoCl 2 K 2 Cr 2 O 7 LPS 6 5 4 3 5 4 3 2 1 NiCl 2 CoCl 2 K 2 Cr 2 O 7 LPS B 1 ELISA ( 5 µm) IL-23 8 6 4 2 4h 8h 12h 18h 24h N=4; p.5, Mann-Whitney Bechara R. et al. J Invest Dermatol. 217

(pg/ml) (pg/ml) (pg/ml) art. I Article 1 Ni 2+ induces the production of IL-23, IL-12p4 and IL-12p7 by human MoDC IL-23 p19 p4 IL-12p7 p35 p4 A 15 1 5 ELISA-24hrs ( 5 µm; NiCl 2 5 µm; CoCl 2 5 µm; K 2 Cr 2 O 7 5 µm; LPS 25 ng/ml) IL-23 IL-12p4 IL-12p7 NiCl 2 CoCl 2 K 2 Cr 2 O 7 LPS 8 7 6 5 4 15 1 5 NiCl 2 CoCl 2 K 2 Cr 2 O 7 LPS 6 5 4 3 5 4 3 2 1 NiCl 2 CoCl 2 K 2 Cr 2 O 7 LPS B ELISA ( 5 µm) C RT-qPCR ( 5 µm) 1 8 6 4 2 IL-23 il-23p19 mrna il-12p4 mrna il-12p35 mrna 1 6 5 Fold induction 8 4 6 4 3 4 2 2 2 1 4h 8h 12h 18h 24h 2h 4h 8h 12h 2h 4h 8h 12h 2h 4h 8h 12h N=4; p.5, Mann-Whitney Bechara R. et al. J Invest Dermatol. 217

CD4 Alexa fluor -treated MoDCs promote IL-17A producing CD4+ T-cells via IL-23 production Co-culture of MoDCs and allogeneic CD4 + T-cells (R=1/1) Restimulation at Day 6 Intracellular cytokine production at Day 9 after Ionomycin/PMA activation Healthy Donor 1 PBMC 1 Restimulation Intracellular staining D6 D9 idc mdc DC-T co-culture (Ratio 1/1) Healthy Donor 2 PBMC Live/Dead AmCyan CD4 + T-cells Bechara R. et al. J Invest Dermatol. 217

-treated MoDCs promote IL-17A producing CD4+ T-cells via IL-23 production Unloaded MoDCs 37.8%.6% treated MoDCs 39.6% 1.99% IFN-g 6.6%.96% 55.8% 2.6% IL-17A % of IL-17A + CD4 + T-cells 6 4 2 # % of IL-17A + IFN- - CD4 + T-cells 3 # 2 1 % of IL-17A + IFN- + CD4 + T-cells 4 # 3 2 1 N=6; p.5, Wilcoxon Bechara R. et al. J Invest Dermatol. 217

-treated MoDCs promote IL-17A producing CD4+ T-cells via IL-23 production Unloaded MoDCs 37.8%.6% treated MoDCs 39.6% 1.99% IFN-g 6.6%.96% 55.8% 2.6% IL-17A % of IL-17A + CD4 + T-cells 6 4 2 # % of IL-17A + IFN- - CD4 + T-cells 3 # 2 1 % of IL-17A + IFN- + CD4 + T-cells 4 # 3 2 1 N=6; p.5, Wilcoxon Bechara R. et al. J Invest Dermatol. 217

(pg/ml) (pg/ml) (pg/ml) art. I Article 1 TLR4 pathway is implicated in -induced IL-23, IL-12p4 and IL-12p7 production IL-23 ELISA-24hrs ( 5 µm) 5 4 3 IL-23 p19 p4 IL-12p7 -TLR-4 -IgG 1h 24h ELISA 2 1 1 5 1 1 5 1 p35 p4 N=4; p.5, Mann-Whitney -IgG g/ml -TLR4 g/ml + 15 IL-12p4 5 IL-12p7 4 1 3 5 2 1 1 5 1 1 5 1 1 5 1 1 5 1 -IgG g/ml + NiSO -TLR4 g/ml Bechara R. et al. J Invest Dermatol. 217 -IgG g/ml + -TLR4 g/ml

The Jak-STAT pathway regulates the IL-23/IL-12p7 balance in -treated MoDCs Ni 2+ TLR4 Jak Ni 2+ STAT-1 IRF-1 IL-12p35 Antonios et al. J immunol. 21 p38 MAPK STAT NF-kB? JAK Inhibitor I (.5 µm) ATP-competitive inhibitor of Janus protein tyrosine kinases (JAKs). IL-23 IL-12p4 IL-12p7

art. I Article 1 The Jak-STAT pathway regulates the IL-23/IL-12p7 balance in -treated MoDCs IL-23 A ELISA-24hrs ( 5 µm; Jak Inhibitor I.5 µm ) 1 25 IL-23 IL-12p4 IL-12p7 4 8 2 3 p19 p4 IL-12p7 (pg/ml) 6 4 (pg/ml) 15 1 (pg/ml) 2 2 5 1 p35 p4 + + + B RT-qPCR-4hrs ( 5 µm; Jak Inhibitor I.5 µm) Fold induction 25 2 15 1 5 il-23p19 mrna il-12p4 mrna il-12p35 mrna 6 5 Fold induction 4 2 Fold induction 4 3 2 1 N=4; p.5, Mann-Whitney Bechara R. et al. J Invest Dermatol. 217 + + +

What are the mechanisms mediating the increase in -induced IL-23 and IL-12p4 production following Jak-STAT inhibition? NFIL-3 (Nuclear Factor, Interleukin 3 Regulated) is a basic leucine zipper transcription factor. NFIL-3 serves as a key regulator in the development and functions of immune cells. NFIL-3 plays a crucial role in various immune-mediated diseases. NFIL-3 Promoter IL-12p4 Kobayashi et al. J immunol. 211 Smith et al. J Biol Chem 211 NFIL-3 -/- IL-23 IL-12p4 Colitis Kobayashi et al. J immunol. 214 NFIL-3 is a transcriptional repressor of IL-12p4 in macrophages and mucosal immunity Kobayashi et al. J immunol. 211 Smith et al. J Biol Chem 211 NFIL-3-deficient macrophages expressed higher IL-12p4 and IL- 23p19 compared to WT Kobayashi et al. J immunol. 214

What are the mechanisms mediating the increase in -induced IL-23 and IL-12p4 production following Jak-STAT inhibition? 1- induces NFIL-3 expression in human MoDCs 4 LPS Fold induction 3 2 1 1h 2h 3h

What are the mechanisms mediating the increase in -induced IL-23 and IL-12p4 production following Jak-STAT inhibition? 1- induces NFIL-3 expression in human MoDCs 4 LPS Fold induction 3 2 1 1h 2h 3h 2- NFIL-3 expression is mediated by the Jak-STAT pathway 4 Jak-STAT Jak-STAT N=4; p.5, Mann-Whitney Fold induction 3 2 1 Comtrol Jak Inhibitor I Jak Inhibitor I + NFIL-3?? IL-12p4 IL-23p19 NFIL-3 IL-12p4 IL-23p19

Conclusions and perspectives -Conclusions: - induces the production of IL-23 and the expression of il-23p19 and il-12p4 mrna, -p38mapk, NF-kB and TLR4 were involved in IL-23 production induced by nickel. -Nickel contributes to NFIL-3 expression in human MoDCs and JAK/STAT limit the production of IL-23 by promoting Th1 polarization -Publications: -Nickel Sulfate Promotes IL-17A Producing CD4+ T Cells by an IL-23-Dependent Mechanism Regulated by TLR4 and Jak-STAT Pathways. Bechara R, Antonios D, Azouri H, Pallardy M. J Invest Dermatol. 217 Oct;137(1):214-2148. doi: 1.116/j.jid.217.5.25. Epub 217 Jun 17. IF =6.28-2 publications in preparation.

Acknowledgements Laboratory of Toxicology-USJ Hayat Azouri Rami Bechara Cynthia Khoury-Abboud Diana Kabbani Maria Bassil Inserm UMR-996-UPSUD Marc Pallardy Rami Bechara Marie-Eliane Azoury Yann Gallais Myriam Nabhan Marie Hullo Natacha Szely Luc de Chaisemartin

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