1. Cell Biology
  2. Immunology and Inflammation

Intestinal goblet cells sample and deliver lumenal antigens by regulated endocytic uptake and transcytosis

  1. Jenny K Gustafsson  Is a corresponding author
  2. Jazmyne E Davis
  3. Tracy Rappai
  4. Keely G McDonald
  5. Devesha H Kulkarni
  6. Kathryn A Knoop
  7. Simon P Hogan
  8. James AJ Fitzpatrick
  9. Wayne I Lencer
  10. Rodney D Newberry  Is a corresponding author
  1. Department of Neuroscience and Physiology, University of Gothenburg, Sweden
  2. Department of Internal Medicine, Washington University School of Medicine, United States
  3. Center for Cellular Imaging, Washington University School of Medicine, United States
  4. Mary H. Weiser Food Allergy Center, University of Michigan School of Medicine,, United States
  5. Department of Cell Biology &Physiology, Washington University School of Medicine, United States
  6. Department of Neuroscience, Washington University School of Medicine, United States
  7. Department of Biomedical Engineering, Washington University in St. Louis, United States
  8. Department of Pediatrics, Harvard Medical School, United States
  9. Division of Gastroenterology, Nutrition and Hepatology, Boston Children’s Hospital, United States
  10. Harvard Digestive Disease Center, Harvard Medical School, United States
https://doi.org/10.7554/eLife.67292
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Cite this article
  1. Jenny K Gustafsson
  2. Jazmyne E Davis
  3. Tracy Rappai
  4. Keely G McDonald
  5. Devesha H Kulkarni
  6. Kathryn A Knoop
  7. Simon P Hogan
  8. James AJ Fitzpatrick
  9. Wayne I Lencer
  10. Rodney D Newberry
(2021)
Intestinal goblet cells sample and deliver lumenal antigens by regulated endocytic uptake and transcytosis
eLife 10:e67292.
https://doi.org/10.7554/eLife.67292
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9 figures, 2 videos, 1 table and 1 additional file

Figures

Figure 1 with 1 supplement
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Goblet cell associated antigen passage (GAP) formation is an active endocytic process dependent on actin polymerization, microtubule transport, and phosphoinositide three kinase (PI3K).

(A) Intravital two-photon imaging, (B) wide-field fluorescent imaging, and (C) super-resolution structured illumination microscopy (SIM) imaging of the small intestine (SI) of CX3CR1GFP (green) or ItgaxYFP (green) reporter mice following luminal administration of 10 kDa tetramethylrodamine (TRITC)-dextran (red) or Texas Red-Ovalbumin (OVA; red). (D) Quantification of GAPs per SI villus cross section in mice treated with vehicle (n = 6), Dyngo 4a (n = 5), dynasore (n = 4), LY294002 (n = 5), cytochalasin D (Cyt D, n = 5), colchicine (n = 6), ciliobrevin D (Cil D, n = 5), or dimethylenastron (DMEA, n = 5) followed by intraluminal administration of 10 kDa TRITC-dextran. (E) Wide-field fluorescent imaging of the SI following intraluminal administration of FM 1–43FX (green) for 1 hr. Goblet cells are visualized by wheat germ agglutinin (WGA-Texas Red) (red). (F) Confocal fluorescent imaging of the SI following intraluminal administration of FM 1–43FX (green) and dextran-Alexa647 (red). (G) Wide-field fluorescent imaging of the SI following intraluminal administration of FM 1–43FX (green) and dextran-Alexa647 (red). Asterisk denotes goblet cell, arrow denotes enterocyte, arrows in zoomed in pictures denotes endosomal structures double positive for FM 1–43FX and dextran-Alexa647 in enterocytes. (H) Wide-field fluorescent imaging of the SI following intraluminal administration of TRITC-dextran (red) stained for early endosome protein 1 (EEA1) (green). Arrows denote endosomal structures double positive for TRITC-dextran and EEA1 in enterocytes. Data are presented as mean ± SEM. **p < 0.01, ***p < 0.001 as compared to vehicle treated mice. Scale bar: (A) 50 µm, (B) 25 µm, (C) 10 µm, (E–H) 25 µm. (C and F) represent 3D projections of obtained z-stacks. Statistical analysis was performed using a one-way ANOVA followed by Dunnet’s post-hoc test. A–B, E, G–H n = 6, C, F n = 4. Each point in panel D represents the average number of GAPs from 25 villi in one mouse.

Figure 1—figure supplement 1
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Effect of goblet cell-associated antigen passage (GAP) inhibition on tissue integrity.

Wide-field fluorescent imaging of small intestine tissues treated with (A) vehicle, (B) Dyngo 4a, (C) dynasore, (D) LY294002, (E) cytochalasin D, (F) colchicine, (G) ciliobrevin D, (H) dimethylenastron (DMEA) followed by intraluminal injection of 10 kDa tetramethylrodamine (TRITC)-dextran. Scale bar 50 µm. n = 6 in A and F, n = 5 in B, D, E, G, n = 4 in C. Arrows denote GAPs.

Figure 2 with 1 supplement
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An ultrastructural model of goblet cell (GC)-associated antigen passage (GAP) formation.

(A) 3D model of the compiled focused ion beam scanning electron microscopy (FIB-SEM) data demonstrating the fates of luminal cargo in a GAP. Green: mucin granules, purple: dextran in the trans-Golgi network (TGN), dark blue: dextran in multi-vesicular bodies (MVBs) and lysosomes, red: dextran in vesicles/endosomes, light blue: nucleus. (B) Representative FIB-SEM images showing dextran localizing to TGN, MVBs, lysosomes, and endosomes/vesicles. (C and D) Wide-field fluorescent imaging of the small intestine (SI) following intraluminal administration of tetramethylrodamine (TRITC)-dextran (red) and stained for Rab3D (green), and 4',6-diamidino-2-phenylindole (DAPI) blue (DNA). (C) Goblet cells (GCs) forming GAPs show redistribution of Rab3D (green) with uptake of lumenal dextran. (D) GCs not forming GAPs show Rab3D localized to secretory granules in the theca. (E) Confocal fluorescent imaging of SI following intraluminal injection of TRITC-dextran (red) stained with wheat germ agglutinin (WGA) (green) and DAPI (blue). Arrows denote vesicular structures double positive for dextran and WGA. (F and G) Transmission electron micrographs of the basolateral area of a GC following administration of intraluminal dextran. The dashed line outlines a GC and the solid outlines an adjacent underlying cell. Arrow denote a dextran-containing structure located at the fusion point of the GC and the adjacent cell. Scale bar: (B and F) 2 µm, (C–D) 10 µm, (E) 5 µm, (G) 500 nm. n = 4 in panel B, n = 5 in panel C, D, E, n = 3 in panel E, F.

Figure 2—figure supplement 1
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Goblet cell-associated antigen passage (GAP) formation is associated with transport of cargo to the lysosome and the trans-Golgi network (TGN).

Confocal fluorescent imaging of intestinal tissue specimens following intraluminal injection of tetramethylrodamine (TRITC)-dextran (red) stained for 4',6-diamidino-2-phenylindole (DAPI) (blue) and (A) the late endosome marker Rab7 (green), (B) the lysosome marker LAMP-1 (green), (C) the TGN marker TGN46 (green) and in (D) the secretory granule marker VAMP-8. Scale bar: A–C = 5 µm, D = 10 µm. Arrows denote areas with overlapping staining patterns of dextran and the respective organelle markers.

Figure 3
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Role of muscarinic acetylcholine receptors (mAChRs) in steady-state goblet cell-associated antigen passage (GAP) formation and mucus secretion in the small intestine (SI) and distal colon.

GAP numbers per (A) SI villus and (B) SI crypt in mice treated with vehicle or the mAChR4 antagonist tropicamide. Mucus content of the (C) SI villus and (D) SI crypt quantified as percentage of wheat germ agglutinin-positive (WGA+) area per villus/crypt area in mice treated with vehicle or tropicamide. (E) Representative wide-field fluorescent image of the SI of mice treated with vehicle or tropicamide following intraluminal administration of tetramethylrodamine (TRITC)-dextran (red) and WGA staining of mucus (green). (F) GAP numbers per distal colon (DC) crypt in mice treated with vehicle, pan muscarinic receptor antagonist atropine, mAChR3 antagonist 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP), or mAChR1 antagonist telenzepine. (G) Representative wide-field fluorescent imaging of distal colon crypts of mice treated with vehicle, atropine, 4-DAMP, or telenzepine following intraluminal administration of TRITC-dextran (red) and Ulex europaeus agglutinin 1 (UEA1) staining of mucus. (H) Mucus content of the distal colon crypt of mice treated with vehicle or 4-DAMP, quantified as percentage of UEA1+ area per distal colon crypt area. Data are presented as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001 as compared to vehicle. n.s. = non-significant as compared to vehicle. n = 5 in panels A–D, n = 6 in panel F (telenzepine n = 5). Each data point in A–D, F, H represents the average of 25 villi or 40 crypts from one mouse. Statistical analysis was performed using an unpaired two-sided Student’s t-test in panel A–D, H. A one-way ANOVA followed by Dunnet’s post hoc test was performed in panel F.

Figure 4
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Carbamylcholine (CCh)-induced goblet cell (GC)-associated antigen passage (GAP) formation and mucus secretion in the small intestine (SI) and distal colon.

(A) GAP numbers, (B) total wheat germ agglutinin-positive (WGA+) (SI) or Ulex europaeus agglutinin 1 (UEA1+) (distal colon) mucus area per villus/crypt area, (C) representative wide-field fluorescent image of SI villus, (D) quantification of the number of WGA+ (SI) or UEA1+ (distal colon) GCs per villus or crypt cross section, (E) quantification of GC theca area, (F) representative wide-field fluorescent image of SI crypts in vehicle and CCh treated tissue. (G) Representative wide-field fluorescent image of distal colon crypts and (H) representative wide-field fluorescent image of an SI crypt following intraluminal tetramethylrodamine (TRITC)-dextran (red) administration stained for Lysozyme (white). Arrows denote a Paneth cell containing TRITC-dextran. Scale bar: (C) 100 µm, (F, J, K) 50 µm. Data are presented as mean ± SEM, *p < 0.05, **p < 0.01, ***p < 0.001, n.s = non-significant, n = 9 in all groups. Statistical analysis was performed using an unpaired two-sided Student’s t-test. Each data point in A–B, D–E represents the average of 25 villi or 40 crypts from one mouse.

Figure 5 with 2 supplements
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Carbamylcholine (CCh)-induced goblet cell-associated antigen passage (GAP) formation and mucus secretion use different muscarinic acetylcholine (ACh) receptors.

Effect of the muscarinic ACh receptor 4 (mAChR4) antagonist tropicamide (Trop.), the mAChR1 antagonist telenzepine (Telenz.), or the preferential mAChR3 antagonist 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP) on CCh-induced mucus secretion and GAP formation in the small intestine (SI) villus (A–B), the SI crypt (C–D), and the distal colon crypt (E–F). Data are presented as mean ± SEM. **p < 0.01, ***p < 0.001, n.s = non-significant, as compared to CCh. A–B, D–E, n = 6 in all groups. (C and F) Vehicle and CCh n = 7, CCh + 4 DAMP and CCh + Telenz. n = 5. Statistical analysis was performed using a one-way ANOVA followed by Dunnet’s post hoc test. Each data point represents the average of 25 villi or 40 crypts from one mouse.

Figure 5—figure supplement 1
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Small intestine expression of muscarinic ACh receptor 4 (mAChR4) and mAchR1.

Confocal fluorescent imaging of (A) mAChR4 and (B) mAChR1 expression in the small intestine using RNAscope. Arrows denote goblet cells staining positive for the mAChR1/4 probes. Scale bar 50 µm. n = 5.

Figure 5—figure supplement 2
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Distal colon expression of muscarinic ACh receptor 3 (mAChR3) and mAChR1.

Confocal fluorescent imaging of (A) mAChR3 and (B) mAChR1 expression in the distal colon using RNAscope. Arrows denote goblet cells staining positive for the mAChR1/3 probes. Scale bar 50 µm. n = 5.

Figure 6 with 1 supplement
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In the small intestine (SI), carbamylcholine (CCh)-induced goblet cell-associated antigen passage (GAP) formation and mucus secretion use different calcium pools and signaling pathways.

Effect of the extracellular Ca2+ chelator EGTA, intracellular Ca2+ chelator BAPTA-AM, IP3R inhibitor Xestospongin C (Xesto C), cADPr inhibitor 8-Br-cADPr, and NAADP inhibitor Trans-Ned-19 (T Ned-19) on CCh-induced mucus secretion in (A) the SI villus, (B) the SI crypt. Effect of Ca2+ signaling inhibitors on CCh-induced GAP formation in (C) the SI villus, (D) the SI crypt. (E–K) Representative images of the effect of the respective treatments on CCh-induced mucus secretion and GAP formation. Scale bar: E–K = 50 µm. Data are presented as mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001, n.s = non-significant as compared to CCh. Vehicle and CCh, n = 7, EGTA and BAPTA-AM n = 5, Xesto C, T-Ned-19, and 8-Br-cADPr n = 6. Statistical analysis was performed using a one-way ANOVA followed by Dunnet’s post hoc test. Each data point in (A–D) represents the average of 25 villi or 40 crypts from one mouse.

Figure 6—figure supplement 1
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Endoplasmatic reticulum (ER) staining in intestinal goblet cell-associated antigen passage (GAPs).

Confocal fluorescent imaging of intestinal tissues following intraluminal injection of tetramethylrodamine (TRITC)-dextran (red) stained with the ER marker calnexin (green). Scale bar 5 µm.

Figure 7
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In the distal colon, carbamylcholine (CCh)-induced goblet cell-associated antigen passage (GAP) formation and mucus secretion use different calcium pools and signaling pathways.

Effect of the extracellular Ca2+ chelator EGTA, intracellular Ca2+ chelator BAPTA-AM, IP3R inhibitor Xestospongin C (Xesto C), cADPr inhibitor 8-Br-cADPr, and NAADP inhibitor Trans-Ned-19 (T Ned-19) on (A) CCh-induced mucus secretion and (B) GAP formation in the distal colon. (C–I) Representative images of the effect of the respective treatments on CCh-induced mucus secretion and GAP formation. Data are presented as mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001, n.s = non-significant as compared to CCh. Vehicle and CCh, n = 7, EGTA and 8-Br-cADPr n = 5, BAPTA-AM, Xesto C, and T-Ned-19 n = 6. Scale bar: C–I = 50 µm Statistical analysis was performed using a one-way ANOVA followed by Dunnet’s post hoc test. Each data point in (A–B) represents the average of 40 crypts from one mouse.

Figure 8
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Carbamylcholine (CCh) induced mucus secretion and goblet cell (GC)-associated antigen passage (GAP) formation can occur in parallel within the same GC.

(A) Average theca area of GCs forming GAPs in vehicle, CCh, and CCh + EGTA treated mice. Size distribution of the theca area of GCs forming GAPs in vehicle, CCh, and CCh + EGTA treated mice in (B) small intestine (SI) villus, (C) SI crypt, and (D) DC crypt. (E) Average theca area of GCs not forming GAPs in vehicle, CCh, and CCh + EGTA treated mice. Size distribution of GCs not forming GAPs in vehicle, CCh, and CCh + EGTA treated mice in (F) SI villus, (G) SI crypt, and (H) DC crypt. Data are presented as mean ± SEM. Vehicle n = 7, CCh n = 7, CCh + EGTA n = 5. Statistical analysis was performed using a one-way ANOVA with Tukey’s post hoc test for multiple comparisons. In panels B–D and F–H, the data represent the percentage of GCs within the respective area bins as part of the total population of GCs forming GAPs, or the total population of GCs not forming GAPs (100%).

Figure 8—source data 1

Tables of raw data for Figure 8B–D and F–H.

https://cdn.elifesciences.org/articles/67292/elife-67292-fig8-data1-v2.xlsx
Figure 9
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Schematic representation of acetylcholine (ACh)-induced mucus secretion and goblet cell-associated antigen passage (GAP) formation in intestinal goblet cells.

In response to exogenous ACh, intestinal goblet cells respond with an accelerated mucus secretory response mediated by muscarinic ACh receptor 1 (mAChR1), and/or induction of fluid-phase bulk endocytosis of secretory granule membrane (GAP formation) mediated by mAChR4 in the small intestine (SI) and mAChR3 in the distal colon. The endocytic vesicles containing luminal fluid-phase cargo are shuttled through the cell for degradation, membrane recycling, and transcytosis to be acquired by lamina proporia mononuclear phagocytes (LP-MNPs). Using separate mAChRs, Ca2+ pools and signaling pathways for the processes of ACh-induced GAP formation and ACh-induced mucus secretion allow these processes to occur independently or in parallel within the same goblet cell forming the basis of how goblet cells can differentially regulate when to maintain the mucus barrier and when to deliver luminal substances to the immune system.

Videos

Video 1
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Animation of the 3D model of the focused ion beam scanning electron microscopy (FIB-SEM) data.

Green: Mucin granules, light blue: nucleus, red: dextran in vesicular and endosomal structures, dark blue: dextran in lysosomes and multi-vesicular bodies (MVBs) and purple: dextran in the trans-Golgi network (TGN).

Video 2
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Animation of the focused ion beam scanning electron microscopy (FIB-SEM) pictures and the corresponding segmentation that the model is based on.

Upper left panel: FIB-SEM pictures, upper right panel: segmentation of the nucleus (blue), mucin granuels (green), dextran in endosomes/vesicles (red), dextran in MVBs and lysosomes (orange). Lower left panel: segmentation of dextran in the trans-Golgi network (TGN) (blue).

Tables

Key resources table
Reagent type (species) or resourceDesignationSource or referenceIdentifiersAdditional information
AntibodyEEA1 (rabbit monoclonal)Cell Signaling TechnologyCat#3288 S, RRID:AB_2096811IF (1:100)
AntibodyLysozyme (rabbit polyclonal)Thermo Fisher ScientificCat#PA5-16668, RRID:AB_10984852IF (1:100)
AntibodyRab3D (rabbit polyclonal)Synaptic systemsCat#107 303, RRID:AB_2253547IF (1:100)
AntibodyRab7 (rabbit monoclonal)Cell Signaling TechnologyCat#9367T, RRID:AB_1904103IF (1:100)
AntibodyLAMP-1 (rabbit polyclonal)AbcamCat#ab62562RRID:AB_2134489IF (1:100)
AntibodyTGN46 (rabbit monoclonal)Thermo FisherCat#MA5-32532RRID:AB_2809809IF (1:100)
AntibodyVAMP8 (chicken polyclonal)University of TexasProf Burton DickeyIF (1:500)
AntibodyCalnexin (rabbit polyclonal)AbcamCat#ab22595RRID:AB_2069006IF (1:100)
AntibodyGoat anti-Chicken IgY Alexa Fluor 555(goat polyclonal)Thermo Fisher ScientificCat#A32932RRID:AB_2762844IF (1:1000)
AntibodyGoat anti-Rabbit IgG Alexa Fluor 488 (goat polyclonal)Thermo Fisher ScientificCat#A-11008, RRID:AB_143165IF (1:1000)
AntibodyGoat anti-Rabbit IgG Alexa Fluor 647 (goat polyclonal)Thermo Fisher ScientificCat#A-21244RRID:AB_2535812IF (1:1000)
Chemical compound, drugAtropineSigma-AldrichCat#A0257550 µg/kg i.p.
Chemical compound, drugTelenzepineSigma-AldrichCat#T122550 µg/kg i.p.
Chemical compound, drug4-DAMPSigma-AldrichCat#SML0255550 µg/kg i.p.
Chemical compound, drugTropicamideTocrisCat#0909100 µg/kg s.c.
Chemical compound, drugCarbamylcholineSigma-AldrichCat#C4382125 µg/kg s.c.
Chemical compound, drugFM 1–43FXThermo Fisher ScientificCat#F3535550 µg/ml
Chemical compound, drugEGTASigma-AldrichCat#E38892 mM
Chemical compound, drugBAPTA-AMSigma-AldrichCat#A1076200 µM
Chemical compound, drugXestospongin CSigma-AldrichCat#X262822 µM
Chemical compound, drugDynasoreSigma-AldrichCat#D7693150 µM
Chemical compound, drugDyngo 4aSelleck ChemicalsCat#S7163120 µM
Chemical compound, drugColchicineTocrisCat#1364100 µM
Chemical compound, drugCytochalasin DTocrisCat#12334 µM
Chemical compound, drugCiliobrevin DSigma-AldrichCat#250401100 µM
Chemical compound, drugDimethylenastron (DMEA)TocrisCat#526110 µM
Chemical compound, drug8-Br-cADPrSigma-AldrichCat#B54160.2 mg/kg i.p.
Chemical compound, drugTrans-Ned19TocrisCat#39545 mg/kg i.p
Chemical compound, drugLY294002Sigma-AldrichCat#L99084 mg/kg i.p
Chemical compound, drugDiamidino-2-phenylindole (DAPI)Sigma-AldrichCat#D95421 µg/ml
Chemical compound, drugUEA1 FluoresceinVector LaboratoriesCat#FL-1061–210 µg/ml
Chemical compound, drugWGA FluoresceinVector LaboratoriesCat#FL-102110 µg/ml
Chemical compound, drugWGA Texas RedSigma-AldrichCat#W2140510 µg/ml
Chemical compound, drugDextran tetramethylrodamine conjugate, lysine fixable, MW 10,000Thermo Fisher ScientificCat#D181712.5 mg/ml
Chemical compound, drugDextran biotin conjugate, lysine fixable, MW 10,000Thermo Fisher ScientificCat#D195612.5 mg/ml
Chemical compound, drugDextran Alexa 647 conjugate lysine fixable, MW 10,000Thermo Fisher ScientificCat#D2291412.5 mg/ml
Chemical compound, drugOvalbumin Texas Red conjugateThermo Fisher ScientificCat#O2302112.5 mg/ml
Chemical compound, drugNi DABVector LaboratoriesCat#SK-4100, RRID:AB_2336382
Commercial assay or kitABC Elite kitVector LaboratoriesCat#PK-6100, RRID:AB_2336819
Commercial assay or kitRNAscope fluorescent reagent kit v2ACD, Bio-TechneCat# 323100
Sequence-based reagentMm-Chrm1-O1-C2ACD, Bio-TechneCat#483441-C2
Sequence-based reagentMm-Chrm3ACD, Bio-TechneCat#437701
Sequence-based reagentMm-Chrm4-C2Chrm4ACD, Bio-TechneCat#410581-C2
Species, species background (Mus musculus)Mouse: C57 Bl/6 JJackson LaboratoriesStock No: 000664, RRID:IMSR_JAX:000664
Species, species background (Mus musculus)Mouse: Itgax YFPJackson LaboratoriesStock No: 008829RRID: IMSR_JAX:008829
Species, species background (Mus musculus)Mouse: Cx3cr1 GFPJackson LaboratoriesStock No: 005582RRID: IMSR_JAX:005582
Software, algorithmGraphPad Prism 7GraphPadhttps://www.graphpad.com, RRID:SCR_002798
Software, algorithmAmiraThermofisherhttp://www.fei.com/software/amira-3d-for-life-sciences/, RRID:SCR_007353
Software, algorithmZenZeisshttp://www.zeiss.com/microscopy/en_us/products/microscope-software/zen.html#introduction, RRID:SCR_013672
Software, algorithmFijiSchindelin et al., 2012https://fiji.sc/, RRID:SCR_002285
Software, algorithmAxioVisionZeisshttp://www.zeiss.com/microscopy/en_de/products/microscope-software/axiovision-for-biology.html, RRID:SCR_002677
Software, algorithmImarisBitplanehttp://www.bitplane.com/imaris/imaris RRID:SCR_007370
Software, algorithmImageWarpA&B Softwarehttp://www.imagewarp.com/

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  1. Jenny K Gustafsson
  2. Jazmyne E Davis
  3. Tracy Rappai
  4. Keely G McDonald
  5. Devesha H Kulkarni
  6. Kathryn A Knoop
  7. Simon P Hogan
  8. James AJ Fitzpatrick
  9. Wayne I Lencer
  10. Rodney D Newberry
(2021)
Intestinal goblet cells sample and deliver lumenal antigens by regulated endocytic uptake and transcytosis
eLife 10:e67292.
https://doi.org/10.7554/eLife.67292