Keratin-dependent thymic stromal lymphopoietin expression suggests a link between skin blistering and atopic disease Vinod Kumar, PhD, Matthias Behr,

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Keratin-dependent thymic stromal lymphopoietin expression suggests a link between skin blistering and atopic disease Vinod Kumar, PhD, Matthias Behr, PhD, Dimitra Kiritsi, MD, Andrea Scheffschick, MSc, Anja Grahnert, PhD, Melanie Homberg, MSc, Agnes Schwieger-Briel, MD, Thilo Jakob, MD, Leena Bruckner-Tuderman, MD, Thomas M. Magin, PhD Journal of Allergy and Clinical Immunology Volume 138, Issue 5, Pages 1461-1464.e6 (November 2016) DOI: 10.1016/j.jaci.2016.04.046 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Loss of keratins or keratin mutation triggers TSLP upregulation via ERK1/2. A, Tslp RNA in WT, KtyI−/−, and KtyII−/− mice skin (n = 2) and protein levels in WT (n = 4) and KtyIIm−/− (n = 6) sera determined by qPCR and/or ELISA. B, Immunofluorescence staining of keratin 5 (K5) (green) and Tslp (red) in KtyIIm−/− mice (n ≥ 3). C, Tslp RNA and protein levels in WT, KtyI−/−, KtyI−/− K14, and KtyI−/− K14R131P examined by qPCR and/or ELISA (n = 3). D, qPCR and Western blot analysis of KtyI−/− cells treated with MEK1/2 inhibitor U0126 and MAPK signaling activator PMA. WT cells treated with conditioned medium of KtyI−/− cells (n = 3). KtyIIm−/−, Keratin type 2 mosaic knockout; ns, nonsignificant; PMA, phorbol-12-myristate-13-acetate; qPCR, quantitative PCR. Error bars represent standard error. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2016 138, 1461-1464.e6DOI: (10.1016/j.jaci.2016.04.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Eight of 17 patients with EBS show elevated TSLP serum level. A, Skin defects (disease severity score EB) are indicated by + (few blisters on hands and feet), ++ (severe blistering on extremities), or +++ (severe, generalized blistering). Elevated TSLP levels (>50 pg/mL) correlate with a high disease score (++, +++). Error bars represent SDs. Correlation and statistical analysis between TSLP level and this severity score are indicated in the top right. *P < .05 and ***P < .001. AD/As/allergy, Atopic dermatitis, asthma or allergy, respectively; CCL17, thymus and activation-regulated chemokine; Fx1, food allergens; na, not available; neg, negative; no, absence; ns, nonsignificant; pos, positive; Sx1, aeroallergens. Itch evaluation = scale from 0 to 10 (0 = no itch; 10 = worst imaginable itch). B, Model of barrier- and keratin-dependent TSLP upregulation induced via calcineurin and IKK or MEK1/2-ERK1/2, respectively. Upon barrier defects induced by filaggrin (FLG) or LEKTI mutations, protease-activated receptor PAR2 is activated by different kallikreins (kallikrein-related peptidase 5/7/14) and acts via Ca2+-calcineurin or IKK to trigger Tslp expression by the transcription factors NFAT or nuclear factor kappa B (indicated with black arrows). Loss of keratins or keratin mutations (keratin aggregates) induce Tslp expression via MEK1/2-ERK1/2 of a so far unknown activation mechanism (indicated with red arrows). IKK, Inhibitor of κB kinase; LEKTI, lympho-epithelial Kazal-type-related inhibitor; NFAT, nuclear factor of activated T cells; PAR2, protease-activated receptor 2. Journal of Allergy and Clinical Immunology 2016 138, 1461-1464.e6DOI: (10.1016/j.jaci.2016.04.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Elevated epidermal Tslp protein levels in the absence of keratins and characterization of keratinocyte cell model. A, Immunofluorescence staining of Tslp in WT and KtyI−/− skin. White dashes underline basement membrane. White bar illustrates epidermal thickness elevated in KtyI−/− skin. Scale bar = 20 μm. B, Mouse keratinocytes stained for K14. Note presence of keratin aggregates in KtyI−/− K14R131P transfectants, presence of normal keratin filaments in KtyI−/− K14 and KtyI WT keratinocytes, and absence in KtyI−/− cells. Quantification of K14 level is indicated. Scale bar = 10 μm. Journal of Allergy and Clinical Immunology 2016 138, 1461-1464.e6DOI: (10.1016/j.jaci.2016.04.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Intracellular calcium signaling contributes to Tslp levels via MAPK signaling in keratinocytes. A and B, Tslp RNA expression in KtyI−/− cells treated with intracellular calcium chelator BAPTA-AM (Fig E2, A) or with extracellular calcium chelator EGTA (Fig E2, B), respectively. C, Tslp RNA expression in KtyI−/− cells treated with BAPTA-AM, MEK1/2 inhibitor U0126, and cotreatment of BAPTA-AM and U0126. Western blot analysis and quantification of ERK1/2 phosphorylation of KtyI−/− cells following BAPTA-AM treatment is indicated. D and E, Quantification of ERK1/2 phosphorylation of KtyI−/− cells treated with U0126 and PMA is indicated (Western blots of Fig 1, D). BAPTA-AM, 1,2-Bis(2-Aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid; n.s., not significant; PMA, phorbol-12-myristate-13-acetate. Asterisks represent P values. *P < .05; **P < .01; ***P < .001. Error bars indicate SEM. Journal of Allergy and Clinical Immunology 2016 138, 1461-1464.e6DOI: (10.1016/j.jaci.2016.04.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 TSLP protein levels from normal controls. Representative TSLP protein levels from normal controls (n = 45, obtained by the Universities of Freiburg and Leipzig [blood bank] were typically below 50 pg/mL [black line]). Note that TSLP protein levels can be enriched in normal controls because of smoking behavior, unspecified infections, and skin lesions. Journal of Allergy and Clinical Immunology 2016 138, 1461-1464.e6DOI: (10.1016/j.jaci.2016.04.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Elevated TSLP levels in patients with EBS correlate with skin lesions. A, EBS patient 7 with basal TSLP levels (see Fig 2, A) has minimal EB-related skin manifestations. B, EBS patient 8 with high TSLP levels (see Fig 2, A) has several blisters on hands and feet (arrows). C-F, Representative immunohistochemical images support ELISA data showing TSLP accumulation (red staining) within the epidermis from patients with EBS when compared with atopic skin and control skin. Note local cytolysis and hyperkeratosis. Scale bar = 50 μm. Journal of Allergy and Clinical Immunology 2016 138, 1461-1464.e6DOI: (10.1016/j.jaci.2016.04.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions