Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4–mediated suppression of IL-10 Susanne Kaesler, PhD, Thomas Volz, MD, Yuliya.

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Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4–mediated suppression of IL-10 Susanne Kaesler, PhD, Thomas Volz, MD, Yuliya.

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Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4–mediated suppression of IL-10 Susanne Kaesler, PhD, Thomas Volz, MD, Yuliya Skabytska, MSc, Martin Köberle, PhD, Ulrike Hein, MD, Ko-Ming Chen, MD, Emmanuella Guenova, MD, Florian Wölbing, MD, Martin Röcken, MD, Tilo Biedermann, MD Journal of Allergy and Clinical Immunology Volume 134, Issue 1, Pages 92-99.e6 (July 2014) DOI: 10.1016/j.jaci.2014.02.017 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 TH2-mediated dermatitis is self-limited and dependent on IL-4 and MHCII. A and B, Intracutaneous OVA-specific TH2 cells mediate dermal inflammation in the ears of naive BALB/c (Fig 1, A) or C57BL/6 (Fig 1, B) mice quantified as changes in ear thickness. C, Transfer of WT or Il4−/− OVA-activated TH2 cells in WT or Il4ra−/− mice (BALB/c background) demonstrated a strict dependence on IL-4. D, Complete abrogation of inflammation in MHCII−/− mice (C57BL/6 background). n = 4-10. #*P < .05, **P < .005, and ***P < .0005. Journal of Allergy and Clinical Immunology 2014 134, 92-99.e6DOI: (10.1016/j.jaci.2014.02.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 TLR2 ligands convert TH2-mediated acute dermatitis into exaggerated and persistent inflammation. A-D, Progression of TH2-induced dermatitis after exposure to TLR2 ligands in BALB/c (Fig 2, A and C) and C57BL/6 (Fig 2, B and D) mice is shown. LTA temporarily enhanced dermatitis (Fig 2, A and B). Pam2 converted dermatitis into persistent inflammation (Fig 2, C and D). E, Representative hematoxylin and eosin staining of histologic sections from C57BL/6 mice 48 hours after intracutaneous transfer. F, Relative IFN-γ mRNA level in ear skin 12 hours after transfer. G and H, OVA-sensitized DO11.10 mice (BALB/c background) challenged intracutaneously with OVA with or without Pam2. Cutaneous inflammation after OVA activation of endogenous TH2 cells is shown in Fig 2, G, and histology (day 6) is shown in Fig 2, H. n = 4-20. *P < .05, **P < .005, and ***P < .0005. Journal of Allergy and Clinical Immunology 2014 134, 92-99.e6DOI: (10.1016/j.jaci.2014.02.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 TLR2 activation of skin cells converts TH2-mediated acute dermatitis to enhanced and prolonged inflammation. A and B, Crossover experiment for persistent inflammation. Fig 3, A, shows Pam2-induced aggravated dermatitis in BALB/c mice after intracutaneous activation of either WT or Tlr2−/− TH2 cells. Fig 3, B, shows self-limited acute dermatitis, as in OVA-treated control animals, despite exposure to Pam2 in Tlr2−/− recipients (done in parallel with Fig 3, A). C, Exacerbation and prolongation of dermatitis after transfer of TH2 cells and Pam2-exposed OVA-pulsed DCs in C57BL/6 mice. D, Pam2-exposed WT but not Tlr2−/− DCs promote exacerbated inflammation in Tlr2−/−-C57BL/6 mice. n = 4-10. **P < .005 and ***P < .0005. Journal of Allergy and Clinical Immunology 2014 134, 92-99.e6DOI: (10.1016/j.jaci.2014.02.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Suppression of TLR2 ligand–induced IL-10 by IL-4. A, DCs exposed to Pam2 produced intermediate levels of IL-12p70 and high levels of IL-10 (left). Coactivation of Pam2-exposed DCs with IL-4 significantly suppressed IL-10 secretion (Fig 4, A, right), resulting in a low IL-10/IL-12p70 ratio (B; average of 4 experiments). **P < .005. Journal of Allergy and Clinical Immunology 2014 134, 92-99.e6DOI: (10.1016/j.jaci.2014.02.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Suppression of IL-10 by coactivation of IL-4R and TLR2 converts acute dermatitis to chronic inflammation. A and B, Quantitative real-time PCR of cutaneous cytokines during conversion to persistent Pam2-induced dermatitis. Fig 5, A, shows Pam2-induced IL-12p40 and IL-10 expression. Fig 5, B, shows reduced IL-10/IL-12p40 ratio in persistent dermatitis. C, Suppression of IL-10 mRNA in Pam2-exposed DCs by means of coculture with activated TH2 cells or the addition of IL-4. D, Reconstitution of IL-10 abrogated Pam2-induced aggravation of dermatitis after intracutaneous transfer of TH2 cells, DCs, and OVA in Il4ra−/− mice. E, A single Pam2 exposure converted TH2-mediated dermatitis into exacerbated chronic inflammation in C57BL/6 mice. n = 6-10. ***P < .0005. Journal of Allergy and Clinical Immunology 2014 134, 92-99.e6DOI: (10.1016/j.jaci.2014.02.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Phenotypic characterization of TH2 cells. Characterization of WT and IL-4–deficient TH2 cells used for intracutaneous transfer, as shown in Fig 2. Secretion of IL-4 (A), IL-13 (B), and IFN-γ (C) was determined by means of ELISA. For comparison, cytokine secretion by TH1 cells is shown. n.d., Not detectable. Journal of Allergy and Clinical Immunology 2014 134, 92-99.e6DOI: (10.1016/j.jaci.2014.02.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Pam2-induced exacerbated inflammation after TH2 cell activation. A, TH2 cells and OVA were transferred into the skin of BALB/c mice. Twenty-four hours later, some mice were additionally exposed to Pam2, which resulted in aggravated inflammation comparable with that seen after simultaneous application of TH2, OVA, and Pam2 (see Fig 2, C; n = 8). B, Ear skin analysis from the experiment depicted in Fig E2, A, showing increased numbers of CD45+ cells in the Pam2-exposed condition. *P < .05 and ***P < .0005. Journal of Allergy and Clinical Immunology 2014 134, 92-99.e6DOI: (10.1016/j.jaci.2014.02.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 TLR2 activation of DCs converts TH2-mediated acute dermatitis to enhanced and prolonged inflammation. Comparable with Fig 3, D, TH2 cells and OVA-pulsed WT or Tlr2−/− DCs with or without Pam2 exposure were transferred into Tlr2−/− BALB/c mice, and ear swelling was measured thereafter. Pam2-exposed WT but not Tlr2−/− DCs promoted exacerbated dermatitis (n = 10). ***P < .0005. Journal of Allergy and Clinical Immunology 2014 134, 92-99.e6DOI: (10.1016/j.jaci.2014.02.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Suppression of IL-10 by IL-4 in Pam2-activated DCs. IL-10 secretion by bone marrow–derived DCs either from a BALB/c background (A and B) or a C57BL/6 background (C and D), as determined by means of ELISA. Addition of IL-4 significantly suppressed Pam2-induced IL-10 in WT DCs (Fig E4, A and C) but not in DCs with defective IL-4 signaling pathways (Fig E4, B and D). n.d., Not detectable. *P < .05 and ***P < .0005. Journal of Allergy and Clinical Immunology 2014 134, 92-99.e6DOI: (10.1016/j.jaci.2014.02.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 IL-4 expression in mouse ear skin. Relative IL-4 mRNA levels in mouse ear skin 12 and 24 hours after transfer of TH2 cells and OVA with or without Pam2, corresponding to expression shown in Fig 5, A and B. Values were determined by using real-time PCR, normalized to β-actin, and shown relative to values obtained after transfer of OVA alone (n=6). Journal of Allergy and Clinical Immunology 2014 134, 92-99.e6DOI: (10.1016/j.jaci.2014.02.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions