Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1+Tac1+ nociceptor–MRGPRB2+ mast cell sensory clusters represents a key early event in the development of allergic skin reactions.
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The data that support the findings of this study are available from the corresponding author upon request.
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We thank all members of the Galli and Gaudenzio laboratories for discussions, and C. Liu for technical assistance. We thank A. Olson and the Stanford Neuroscience Microscopy Service (supported by NIH No. NS069375); this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the NIH. We thank F. L’Faqihi (IFR30, Plateau Technique Cytometrie, Toulouse) and S. Allart (IFR30, Plateau Technique Imagerie Cellulaire, Toulouse) for technical assistance. T.M. is a Research Associate of the F.R.S.-FNRS and is supported by an ‘Incentive Grant for Scientific Research’ of the F.R.S.-FNRS (No. F.4508.18), by the FRFS-WELBIO under grant No. CR-2017 s-04, by the Acteria Foundation and by an ERC Starting Grant (No. IM-ID 801823). P.S. acknowledges support from and the Austrian Science Fund (No. P31113-B30). L.L.R. acknowledges support from the European Commission (Marie Sklodowska-Curie Individual Fellowship No. H2020-MSCA-IF-2014 656086) and the INSERM ATIP-Avenir program. This work was supported by grants from NIH (S.J.G., grant Nos. U19 AI104209, R01 AR067145 and R01 AI32494), the United States–Israel Binational Science Foundation (No. 2013263) and the Sean N. Parker Center for Allergy and Asthma Research, Stanford University (to S.J.G.); and by the Société Française de Dermatologie, the Société Française d’Allergologie, the Marie Sklodowska-Curie Individual Fellowship (H2020-MSCA-IF-2016, No. 749629), the European Research Council (ERC-2018-STG, No. 802041) and the INSERM ATIP-Avenir program (to N.G.).
The authors declare no competing interests.
Peer review information Ioana Visan was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Integrated supplementary information
Supplementary Figure 1 D. farinae and SEB treatment induces the development of systemic D. farinae-specific type 2 immunity and AD-like pathology.
a, Protocol to induce D. farinae + SEB-mediated allergic skin inflammation. b, Clinical score calculation. c-e, WT mice were treated with SEB, D. farinae or D. farinae + SEB (or vehicle control) to induce the development allergic skin inflammation. Representative hematoxylin & eosin (H&E) staining of vehicle-, SEB-, D. farinae-, or D. farinae + SEB-treated areas. d, Clinical score (0-12) of vehicle- (n = 3 mice), SEB-(n = 5 mice), D. farinae-(n = 5 mice), or D. farinae + SEB-treated (n = 5 mice) areas from two independent experiments, mean ± SEM. e, Spleen weight measurements of vehicle- (n = 6 mice) or D. farinae + SEB-treated (n = 15 mice) mice from five independent experiments. f, Flow cytometry analysis of the proportion (%) of splenic CD4+ T lymphocytes from vehicle- (open bars) or D. farinae + SEB-treated (black bars) mice expressing intracellular IL-4, IL-5, IL-13 or IFN-γ after ex vivo restimulation with D. farinae, from vehicle- (n = 5 mice) or D. farinae + SEB-treated (n = 7 mice) mice from three independent experiments, mean + SEM; two-tailed, unpaired t-test, **P<.01 ***P<.001. g,h, WT mice were treated with D. farinae + SEB and injected intraperitoneally twice a week with an anti-mouse IL-4/13Rα blocking antibody (n=6 mice) or an isotype control (n = 6 mice), data are from two independent experiments. g, Representative H&E staining of D. farinae + SEB-treated areas. h, Clinical score (0-12), isotype control-treated vs. anti-IL-4/13Rα-treated D. farinae + SEB-treated, mean + SEM; two-tailed, unpaired t-test, *P<.05. c,g, dotted black lines indicate the junction epidermis/dermis, bars = 100 μm. Each open circle = one mouse. i, Publicly available microarray gene expression data of Trpv1, Tac1 and Trpa1 in mouse DRG and different immune cell subpopulations (GSE 10246); data are shown using a heat map of mRNA expression levels.
Representative confocal microscopy of back skin sections (a,c,e,g,i,k) and corresponding fluorescence analysis (b,d,f,h,j,l) of the indicated staining. Bars = 100 μm; dotted white lines indicate the epidermal/dermal junction. Each open circle = one mouse. Open bars: WT mice treated either with vehicle (n = 5 mice) or D. farinae + SEB (n = 14 mice); black bars: Tac1-/- mice treated with D. farinae + SEB (n = 8 mice); from three independent experiments, mean + SEM; 1-way ANOVA with Tukey’s test for multiple comparisons; *P<.05 **P<.01 ***P<.001.
Supplementary Figure 3 Extended analysis of epidermal protein organization in DMSO-treated and RTX-treated mice.
a, 4-week-old C57BL/6J WT mice were treated subcutaneously (s.c.) into the back with DMSO (Mock treated) or RTX in three escalating doses (30, 70 and 100 μg.kg-1) on consecutive days and mice were rested for 4-6 weeks before D. farinae + SEB treatment. b, Confirmation of TRPV1+ nociceptors ablation by immersion of the tail into a water bath maintained at 52oC17 and comparison of the latency to the first tail movement elicited by hot water in DMSO-treated (open bars, n = 4 mice) vs RTX-treated (black bars, n = 5 mice) group, from two independent experiments, mean + SEM; two-tailed, unpaired t-test, *P<.05. c-p, Representative confocal microscopy from two independent experiments of back skin section (c,e,g,i,k,m,o) and corresponding fluorescence analysis (d,f,h,j,l,n,p) of the indicated staining. Bars = 100 μm; dotted white lines indicate the epidermal/dermal junction. Each open circle = one mouse. All the following groups are D. farinae + SEB-treated, open bars: Mock DMSO-treated mice (n = 4 mice), black bars: RTX-treated mice (n = 5 mice); from two independent experiments mean + SEM; two-tailed, unpaired t-test, *P<.05 **P<.01.
Supplementary Figure 4 D. farinae-mediated activation of DRG neurons is not dependent on MyD88 or PAR-2 signaling and analysis of the proteolytic activity of D. farinae and/or SEB.
DRG neurons were isolated from WT mice then treated with control or MyD88 inhibitory peptide or from PAR-2-deficient mice (a,b). a, Representative Fluo-4 fields of ex vivo cultured DRG neurons from WT mice, incubated with control peptide (a, up) or MyD88 inhibitory peptide (a, mid) or from PAR-2-deficient mice (a, low) and treated with vehicle, 5 ng/ml D. farinae, or 50 mM KCL. Bars = 50 μm. b, Proportion of responding DRG neurons incubated with control peptide (white bars, n = 6 mice) or MyD88 inhibitory peptide (grey bars, n = 6 mice) or from PAR-2-deficient mice (black bars, n=8 mice) stimulated with 5 ng/ml D. farinae and expressed as % of DRG neurons responding to 50 mM KCL, each open circle = one mouse. (a,b) Data are from three independent experiments, (b) mean + SEM. c, Proteolytic activity of D. farinae extracts in presence of SEB or SEB alone and normalized to the 100% proteolytic activity obtained in the control condition D. farinae, from three independent experiments, mean + SEM.
Supplementary Figure 5 Kit-dependent and Kit-independent mast cell-deficient mice are protected from the development of a model of allergic skin inflammation.
Kit-dependent KitW-sh/W-sh mast cell-deficient mice versus Kit+/+ mast cell-sufficient littermate control mice (a-i) and Kit-independent Cpa3-cre+;Mcl-1fl/fl mast cell-deficient mice and Cpa3-cre+;Mcl-1+/+ mast cell-sufficient littermate control mice (j-r) were treated with D. farinae + SEB to induce the development allergic skin inflammation. a, Representative H&E staining of D. farinae + SEB-treated areas. b, Clinical scores (0-12), open circles: Kit+/+ mice (n = 8 mice), closed circles: KitW-sh/W-sh mice (n = 8 mice), from three independent experiments, mean ± SEM, two-tailed, unpaired t-test, ***P<.001. c, Epidermal thickness (μm). d,e, Number of eosinophils (d) and neutrophils (e) in skin sections. f-i, Representative confocal microscopy of back skin section (f,h) and fluorescence analysis (g,i) of claudin-1 (f,g) and filaggrin (h,i) stainings. Bars = 100 μm, dotted black (a) or white (f,h) lines indicate the junction epidermis/dermis. c-e,g,i, Each open circle = one mouse; white bars: Kit+/+ mice (number of mice [c-e] n = 7, [g] n = 6, [i] n = 8), black bars: KitW-sh/W-sh mice (number of mice [c-e] n = 7, [g-i] n = 8) from three independent experiments, mean ± SEM; two-tailed, unpaired t-test, *P<.05 **P<.01 ***P<.001. (j-r) same experiment as in (a-i) but in Kit-independent Cpa3-cre+;Mcl-1fl/fl mast cell-deficient mice and Cpa3-cre+;Mcl-1+/+ mast cell-sufficient littermate control mice. Each open circle = one mouse, open symbols or bars: Cpa3-cre+;Mcl-1+/+ mice (n = 4 mice), black symbols or bars: Cpa3-cre+;Mcl-1fl/fl mice (n = 4 mice); from two independent experiments mean + SEM; two-tailed, unpaired t-test, *P<.05.
Supplementary Figure 6 RTX-treated, Tac1-/- or Mrgprb2mut/mut mice are not deficient in skin mast cell.
a,b, Representative Toluidine blue (TB) staining (a) and associated mast cell counts (b) of D. farinae + SEB-treated area in Kit+/+ (n = 8 mice) and KitW-sh/W-sh mice (n = 7 mice), from three independent experiments. c,d, Same experiment in Cpa3-cre+;Mcl-1+/+ mice (n = 5 mice) and Cpa3-cre+;Mcl-1fl/fl mice (n = 5 mice), from two independent experiments. b,d, mean + SEM; two-tailed, unpaired t-test, *P<.05 ***P<.001. e,f, Same experiment but in vehicle-treated WT mice (open bar, n = 5 mice) or D. farinae + SEB-treated WT (open bars, n=7 mice, from three independent experiments), DMSO-treated (light grey bars n = 4 mice, from two independent experiments), RTX-treated (dark grey bars n = 5 mice, two independent experiments) and Tac1-/- mice (black bars, n = 7 mice, from three independent experiments). g,h, Same experiment but in untreated or D. farinae + SEB-treated in Mrgprb2+/+ mice (n = 6 mice) and Mrgprb2mu/mutt mice (n = 7 mice) (f,h). Mean + SEM; two-tailed, 1-way ANOVA with Tukey’s test for multiple comparisons. Each open circle = one mouse.
Supplementary Figure 7 Extended analysis of epidermal protein organization in Mrgprb2+/+ and Mrgprb2mut/mut mice.
Representative confocal microscopy, of back skin section (a,c,e,g,i,k) and corresponding protein fluorescence analysis (b,d,f,h,j,l) of the indicated staining. Bars = 100 μm; dotted white lines indicate the junction epidermis/dermis. Each open circle = one mouse. All the following groups are D. farinae + SEB-treated, white bars: Mrgprb2+/+ mice ([b,h,j] n = 6, [d] n = 3, [f,l] n = 6 mice), black bars: Mrgprb2mut/mut mice ([b,f,h,j,l] n = 6, [d] n = 3 mice); all from three independent experiments, mean + SEM; two-tailed, unpaired t-test, *P<.05 **P<.01 ***P<.001.
Supplementary Figure 8 Imaging methods used ex vivo and in vivo, pretreatment with E64 prevents ear swelling and AD antigens do not activate mast cells in vitro.
a, Protocol to analyze release of mast cell granules ex vivo in whole-mounted ear skin (related to Figure 5). 8 µg of sulforhodamine 101-labeled avidin (Av.SRho) in 20 μl PBS were intradermally (i.d.) injected into the ear pinna of WT, Mrgprb2mut/mut, or RTX-treated mice and their respective control mice to selectively label mast cell secretory granules in vivo37. 1 week later, ear thickness was measured and right ear pinnae were injected i.d. with 1 µg D. farinae + 50 ng SEB or 1 µM Capsaicin. In some experiments, right ear pinnae were injected i.d. with 1 µg D. farinae + 50 ng SEB with 15 µg of IgG anti-SP. Left ear pinnae were injected with control solutions: vehicle alone or vehicle in combination with IgG isotype. 45 minutes later, ear thickness was measured again and mice were euthanized before ear excision. 3-D images of untouched whole-mounted ears were acquired using volumetric confocal microscopy. b, 1 µg D. farinae + 50 ng SEB alone or pretreated with cysteine protease inhibitor E64 for 30 minutes at 37°C were injected respectively into the left and right ear pinna of each WT mouse (so that each mouse is its own control) in 20 μl PBS. 45 minutes later, ear thickness was measured. c, Changes (Δ) in ear thickness over time after i.d. injection of stimuli, untreated, white circles n = 10 mice and E64-pretreated, n = 10 mice, from two independent experiments, mean ± SEM, two-tailed, paired t-test, *P<.05. Each open circle = one mouse. d, β-hexosaminidase release from human mast cells (hMC) upon treatment with increasing concentrations of D. farinae and SEB, alone or together. For positive control, hMCs were sensitized with human IgE and then stimulated with 10 ng/mL anti-IgE. n = 6 independent experiments with three independent donors, mean + SEM, one-way ANOVA with Tukey’s test for multiple comparisons, ***P<.001. e, β-hexosaminidase release from mouse BMCMCs upon treatment with increasing concentrations of D. farinae and SEB, alone or together. For positive control, BMCMCs were sensitized with murine anti-DNP IgE and then challenged with 10 ng/mL DNP-BSA, n = 8 independent experiments, with BMCMCs from four mice, mean + SEM, one-way ANOVA with Tukey’s test for multiple comparisons ***P<.001. f, Protocol to analyze sensory neuron calcium levels and mast cell granules release simultaneously in living mice. 8 μg of Av.SRho in 20 μl of PBS were injected i.d. into the ear pinna of Pirt-GCaMP3 mice. 1 week later, mice were injected i.d. with vehicle, 1 μM capsaicin, 1 μg D. farinae and 50 ng SEB (used alone or in combination) in a final volume of 20 μl then placed under the two-photon microscope. 3-D images from three independent experiments were acquired and fluorescence corresponding to Av.SRho+ mast cell granule structures or GCaMP3+ neuron calcium levels were analyzed using ImageJ and/or Imaris Bitplane software. g, Examples of mean fluorescence intensity (MFI) detected in vehicle (left) and capsaicin-activated (i.e., with non-degranulated mast cells, right) sensory neurons. h, Examples of Av.SRho+ mast cells without (left) or with (i.e., degranulated mast cells, right) exteriorized mast cell granule structures.
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Serhan, N., Basso, L., Sibilano, R. et al. House dust mites activate nociceptor–mast cell clusters to drive type 2 skin inflammation. Nat Immunol 20, 1435–1443 (2019) doi:10.1038/s41590-019-0493-z
Identification of Gain and Loss of Function Missense Variants in MRGPRX2’s Transmembrane and Intracellular Domains for Mast Cell Activation by Substance P
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