The molecular basis for the propensity of a small number of environmental proteins to provoke allergic responses is largely unknown. Herein, we report that mite group 13 allergens of the fatty acid-binding protein (FABP) family are sensed by an evolutionarily conserved acute-phase protein, serum amyloid A1 (SAA1), that promotes pulmonary type 2 immunity. Mechanistically, SAA1 interacted directly with allergenic mite FABPs (Der p 13 and Blo t 13). The interaction between mite FABPs and SAA1 activated the SAA1-binding receptor, formyl peptide receptor 2 (FPR2), which drove the epithelial release of the type-2-promoting cytokine interleukin (IL)-33 in a SAA1-dependent manner. Importantly, the SAA1–FPR2–IL-33 axis was upregulated in nasal epithelial cells from patients with chronic rhinosinusitis. These findings identify an unrecognized role for SAA1 as a soluble pattern recognition receptor for conserved FABPs found in common mite allergens that initiate type 2 immunity at mucosal surfaces.
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We thank M. C. de Beer (University of Kentucky Medical Center, KY, US) for providing the Saa−/− mice; E. Schmidt and R. Zeiner for animal care; and Z. Lijie, D. Trapin and S. Kickmaier for expert technical assistance. We also thank M. Marlovics (dsgn&cde; firstname.lastname@example.org) for the graphic designs in Figs. 5 and 8 and C. Zwicker for critically reading the manuscript and for helpful discussion and suggestions. This work was funded by the National Institute of Allergy and Infectious Diseases (grants U19AI070235 and R01 AI083315 to M.W.-K.) and the NIH (grants R56AI118791 and R01AI127644 to S.L. and R01AI132590 to A.P.L.) as well as the Austrian Science Fund (DK W1248 and SFB F4609 to W.F.P.). U.S. was supported by an Erwin Schrödinger Fellowship (J3332-B21) of the Austrian Science Fund, a research grant of the American Thoracic Society and DK W1248. N.G. was supported by an NIEHS 5T32ES007141 grant. E.M. was supported by the Austrian National Bank (17600). J.D. was supported by Operational Programme Research, Development and Education, the Call International Mobility of Researchers – MSCA – IF (CZ.02.2.69/0.0/0.0/17_050/0008014). J.C. was supported by the Canadian Institutes of Health Research (DC0190GP).
The authors declare no competing interests.
Peer review information L. A. Dempsey was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
a, Model of allergen-induced airway hyperresponsiveness (AHR) for wild-type (WT) and Saa–/– mice (both C57BL/6 background). Mice were sensitized i.t. on day 0 (1 μg) and i.n. on days 7-11 with 10 μg of HDM extract. Airway measurements were performed 72 h after the last allergen challenge (used in Fig. 1a–j and Extended Data Figs. 2 and 3). b, For SAA1 antibody blockade, we used an established mouse model of allergen-induced AHR sensitizing WT BALB/cJ mice i.t. on day 0 and 14 with 100 µg of HDM extract + isotype control, or HDM + anti-SAA. Airway measurements and tissue harvests were performed 72 h after the last allergen challenge (used in Extended Data Fig. 4). c, In short-term exposure protocols WT and Saa–/– mice (both C57BL/6 background) received a single HDM challenge (100 μg) were sacrificed 16 h later. d, In short-term exposure protocols BALB/cJ mice received a single HDM challenge (100 μg) + isotype control, HDM challenge + HDL (200μg) and isotype control, or HDM + anti-SAA and were sacrificed 24 h later (used in Fig. 2e). e, For overexpression of SAA1 in vivo, mice were injected 20 µg of DNA complexed to polyethylenimine at day 0, exposed to PBS or HDM 48 h later and ILC2s as well as BAL cytokines measurements were performed on day 3 (used Fig. 2f). f, WT and Saa−/− mice were sensitized i.t. on day 0 (1 μg) and i.n. on days 7-11 with 10 μg with extracts from the parasitic worm Schistosoma mansoni (a Puerto Rican isolate). Tissues were harvested 72 h after the last allergen challenge (used in Fig. 4). g, For FPR2 blockade (WRW4, 2 mg/kg), WT BALB/cJ mice were sensitized and challenged i.t. on day 0 and 14 with 100 μg of HDM extract. Airway measurements were performed 72 h after the last allergen challenge (used in Fig. 7a–f). h, In short term exposure experiments, BALB/cJ mice received a single HDM challenge (100 μg) or HDM + WRW4 and were sacrificed 24 h later (used in Fig. 7g, h). i, Model of A. alternata (Alt a)-induced airway inflammation for WT and Saa–/– mice. Mice were sensitized i.t. on day 0 (1 μg) and i.n. on days 7-11 with 10 µg of Alt a extract. Tissues were harvested 72 h after the last allergen challenge (used in Extended Data Fig. 9f–j).
Allergic phenotype in WT and Saa–/– C57BL/6 mice sensitized and challenged with PBS or HDM was analyzed seventy-two hours after the last challenge. a, Lung cell gating strategy used in Fig. 1, Fig. 4 and Extended Data Figs. 6 and 9. Frequency of dendritic cell (DC) populations (b-d), monocytes (e-f) and granulocytes (g-h) in the lungs of WT and Saa–/– mice used in Fig. 1. Data represent means ± s.e.m. of pooled data from 2 independent experiments containing n=11 WT PBS, n=12 WT HDM, n=11 Saa–/– PBS and n=13 Saa–/– HDM animals per group. P values were calculated with a two-tailed test using one-way analysis of variance (ANOVA) with Dunett’s post hoc analysis that compares WT HDM to counterparts. **P = 0.0039, ****P ≤ 0.0001.
Extended Data Fig. 3 Reduced migration of CD3+CD4+ T cells to the lungs of Saa–/– mice after allergen exposure.
Allergic phenotype in WT and Saa–/– C57BL/6 mice sensitized and challenged with PBS or HDM was analyzed seventy-two hours after the last challenge. a, ILC and T cell gating strategy (used in Fig. 1g, h, Fig. 4b–e and Extended Data Fig. 9h–j). b, Total lung cell counts (**P = 0.0073), (c) frequency and (d) numbers of CD3+CD4+ T cells (**P = 0.0014) and (e) frequency and numbers of (f) ICOS+ST2+ ILCs in the lungs of WT and Saa–/– mice. Data represent pooled data presented as means ± s.e.m. from 2 independent experiments containing n=11 WT PBS, n= 12 WT HDM, n=11 Saa–/– PBS and n=13 Saa–/– HDM animals per group. P values were calculated with a two-tailed test using one-way analysis of variance (ANOVA) with Dunett’s post hoc analysis that compares WT HDM to counterparts.
a, AHR (*P = 0.0105), (b) total serum IgE concentrations (*P = 0.0265), (c) eosinophil infiltration into the lungs, and (d) PAS stained lung sections of isotype (iso), HDM+isotype (HDM), or HDM+SAAab-treated (anti-SAA) WT BALB/c mice. Antibodies were administered at 5 μg/i.t. Frequency of (e) Lin−CD45+ST2+IL-13+ ILC2s (**P = 0.0027, ***P = 0.0002), (f) TH2 and (*P = 0.0260, ***P = 0.0001) (g) TH17 cells (*P = 0.0149, ***P = 0.0005) in the lungs of these mice. Data represents means ± s.e.m. of pooled data from 2 independent experiments containing (a) n=6 PBS+iso, n=7 HDM+iso, n=9 HDM+anti-SAA animals per group; (b, c, f, g) n=9 PBS+iso, n=11 HDM+iso, n=13 HDM+anti-SAA animals per group or are representative of 2 independent experiments with (e) n=4 PBS+iso, n=5 HDM+iso, n=7 HDM+anti-SAA animals per group. P values were calculated with a two-tailed test using one-way analysis of variance (ANOVA) with Dunett’s post hoc analysis that compares HDM to iso and anti-SAA counterparts. ****P ≤ 0.0001.
Extended Data Fig. 5 SAA1 is a pattern recognition molecule for mite-derived and human cytosolic FABPs.
a, Migration of SAA1 (1 mg/ml) in IMDM media was analyzed in the presence of the mite FABP rBlo t 13 (1 mg/ml) by native PAGE followed by immunoblot analysis using a sequence-specific antiserum (amino acid 89-104) raised against human SAA1. b, Effects of the protein synthesis inhibitor cycloheximide on IL-33 concentrations in BEAS-2B cells treated for 30 min with HDM (100 μg/ml). c, Cell viability of BEAS-2B cells after HDM exposure over time as measured by continuous reduction of a cell viability substrate by viable cells (**P = 0.0041). SAA1 concentrations in cells after (d) siRNA-mediated silencing of SAA1 (siSAA1) or non-targeting scrambled siRNA (siNT). Effects of SAA1 on HDM-induced IL-6 (**P = 0.0086, ***P = 0.0007) and IL-8 release in cells with siRNA mediated knockdown of SAA1 (siSAA1) (e and f). g, HDM-induced IL-6 amounts after Der p 13-depletion and/or neutralization using a monoclonal antibody specific for mite group 13 allergens (anti-group 13). Data are shown as means ± s.e.m. and are representative of 2 (b, e) or 3 (c) independent experiments or pooled data from 2 independent experiments (d, f) each containing at least n=4 biologically independent samples. Representative analysis of SAA1 migration patterns in the presence of Blo t 13 using sequence-specific rabbit antiserum raised against human SAA1 (aa 89-104) (a). IL-6 amounts were analysed for one representative experiments with n=5 biologically independent samples (g). Cropped images are shown. P values were calculated with a two-tailed test using one-way analysis of variance (ANOVA) followed by Dunett’s post (b) or Tukey’s hoc analysis (e,f), two-way ANOVA followed by Dunnet correction (c) or Student’s t-test (d, g). ***P ≤ 0.001; ****P ≤ 0.0001.
a, Total IgE serum concentrations and numbers of BAL (b) eosinophils and (c) T cells in WT BALB/c mice undergoing a full allergen-exposure protocol using HDM that was depleted using either an isotype control antibody or a monoclonal antibody specific for mite group-13 allergens. d, Numbers of mediestinal lymph node IL-13+ CD4+ T cells (n.d., not detected) and (e) lung ILC2 (*P = 0.029). f-g, Cytokine production from HDM-restimulated lung cells (*P = 0.024). Data represent mean ± s.e.m. of n=2 PBS, n=4 HDM-isotype depleted, n=4 HDM- anti-group 13-depleted comparing HDM-isotype to α-group 13-depleted extract group using two-tailed unpaired t-test.
a, mRNA and (b) protein amounts of SAA in response to HDM (100 μg/ml). c, SAA1 hexamer after rBlo t 13 stimulation was analyzed as described in Fig. 5b. d, Bar graph represents quantitative analysis of SAA hexamer using LI-COR Image Studio Software. e, Concentration-dependent IL-33 release from BEAS-2B cells induced by rBlo t 13. Data are shown as means ± s.e.m. and are pooled data from 2 independent experiments (b, e) each containing n=4-5 replicate wells or representative of 2-3 independent experiments (d). SAA1 mRNA expression, normalized to the average of housekeeping genes, is presented as mean value ± s.e.m. (n = 5). Immunoblot is representative of an experimental n=2. Cropped images are shown. P values were calculated with a two-tailed test using Student’s t-test (a), two-way analysis of variance (ANOVA) followed by Dunnet’s correction (b) or one-way ANOVA with Dunett’s post hoc analysis (d, e). ****P ≤ 0.0001.
a, mRNA expression of the FPR family members FPR1, FPR2 and FPR3 at baseline (filled bars) or after 2 h of HDM stimulation (white bars). b, HDM-triggered IL-33 amounts in BEAS-2B cells overexpressing human FPR1 (**P = 0.0068, ***P = 0.0003). c, IL-33 secretion in BEAS-2B cells overexpressing human FPR2 or cells transfected with an empty vector (EV; pcDNA3.1) (**P = 0.0028). HDM-induced IL-6 and IL-8 amounts in BEAS-2B cells overexpressing FPR2 (d and e) or blocking the FPR2 receptor f (**P = 0.0043) and g (**P = 0.0021)) using WRW4. Data presented as means ± s.e.m. and is representative of 2 independent experiments each containing at least n= 4 biologically independent samples (b, d, f) or pooled data from 2 independent experiments (c, e, g). mRNA expression, normalized to the average of housekeeping genes, is presented as mean values ± s.e.m. (n = 5 biologically independent samples) performed in duplicates (a). P values were calculated with a two-tailed test using Student’s t-test (a) or one-way analysis of variance (ANOVA) with Tukeys multiple comparison test (b-e) or Dunett’s post hoc analysis (f, g). ****P ≤ 0.0001.
a, Immunoblot of SAA1 after A. alternata (Alt a) stimulation of BEAS-2B cells performed as described in Fig. 5b. Alt a-induced IL-33 and IL-8 (**P = 0.0044) secretion in BEAS-2B cells after siRNA-mediated silencing of SAA1 (siSAA1) (b and c) or WRW4-mediated FPR2 blockade (d and e). f, Total serum IgE concentrations, (g) eosinophil numbers and frequency of (h) CD3+CD4+, (i) TH2 and (j) TH17 cells in the lungs of PBS or Alt a-treated WT and Saa–/– C57BL/6 mice. Immunoblots are representative of an experimental n=2 (a). Data are presented as means ± s.e.m. and represent pooled data from 2 independent experiments (b, d, e, f, g, i, j) or show one representative experiment (c) each containing at least n= 4 biologically independent samples or n=8 WT PBS, n=13 WT Alt a, n=8 Saa–/– PBS and n=11 Saa–/– Alt a animals per group (f, g, i, j) or n=5 WT PBS, n=9 WT Alt a, n=5 Saa–/– PBS and n=7 Saa–/– Alt a animals per group (h). Cropped images are shown. P values were calculated with a two-tailed test using one-way analysis of variance (ANOVA) with Tukeys multiple comparison test (a, b) or Dunett’s post hoc analysis (d-j). ****P ≤ 0.0001 siNT = non-targeting siRNA; siSAA1 = SAA1-targeting siRNA. ns=not significant.
Basal (a) SAA1 and (b) FPR2 expression in bronchial epithelial cells from individuals with asthma and matched controls. Data represents means ± s.e.m. of (a and b) n= 6 control and n= 6 individuals with asthma per group. P values were calculated with a two-tailed test using Student’s t-test with Welch’s correction.
Unprocessed immunoblots of Fig. 3.
Unprocessed immunoblots of Fig. 5.
Unprocessed immunoblots of Fig. 8.
Unprocessed immunoblots of Extended Data Fig. 5.
Unprocessed immunoblots of Extended Data Fig. 7.
Unprocessed immunoblots of Extended Data Fig. 9.
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Smole, U., Gour, N., Phelan, J. et al. Serum amyloid A is a soluble pattern recognition receptor that drives type 2 immunity. Nat Immunol 21, 756–765 (2020). https://doi.org/10.1038/s41590-020-0698-1
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