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A Metabolite-Triggered Tuft Cell-ILC2 Circuit Drives Small Intestinal Remodeling
Open accessAbstract
The small intestinal tuft cell-ILC2 circuit mediates epithelial responses to intestinal helminths and protists by tuft cell chemosensory-like sensing and IL-25-mediated activation of lamina propria ILC2s. Small intestine ILC2s constitutively express the IL-25 receptor, which is negatively regulated by A20 (Tnfaip3). A20 deficiency in ILC2s spontaneously triggers the circuit and, unexpectedly, promotes adaptive small-intestinal lengthening and remodeling. Circuit activation occurs upon weaning and is enabled by dietary polysaccharides that render mice permissive for Tritrichomonas colonization, resulting in luminal accumulation of acetate and succinate, metabolites of the protist hydrogenosome. Tuft cells express GPR91, the succinate receptor, and dietary succinate, but not acetate, activates ILC2s via a tuft-, TRPM5-, and IL-25-dependent pathway. Also induced by parasitic helminths, circuit activation and small intestinal remodeling impairs infestation by new helminths, consistent with the phenomenon of concomitant immunity. We describe a metabolic sensing circuit that may have evolved to facilitate mutualistic responses to luminal pathosymbionts.
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“Tissue and circulating succinate is also elevated in other chronic inflammatory settings such as models of diet-induced obesity8.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [8]
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From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites
Koh, A., De Vadder, F., Kovatcheva-Datchary, P., & Bäckhed, F. (2016) · Cell · doi:10.1016/j.cell.2016.05.041 · Cited by 7,070
The gut microbiota--masters of host development and physiology
Sommer, F., & Bäckhed, F. (2013) · Nature Reviews Microbiology · doi:10.1038/nrmicro2974 · Cited by 3,681
Innate lymphoid cells — a proposal for uniform nomenclature
Spits, H., Artis, D., Colonna, M., Diefenbach, A., Disanto, J. D., Eberl, G., Koyasu, S., Locksley, R., McKenzie, A., Mebius, R., et al. (2013) · Nature reviews. Immunology · doi:10.1038/nri3365 · Cited by 2,380
Self-citationMills, E. L., Kelly, B., Logan, A., Costa, A. S. H., Varma, M., Bryant, C. E., Tourlomousis, P., Däbritz, J. H. M., Gottlieb, E., Latorre, I., et al. (2016) · Cell · doi:10.1016/j.cell.2016.08.064 · Cited by 2,291
Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity
Neill, D. R., Wong, S. H., Bellosi, A., Flynn, R. J., Daly, M. G., Langford, T. K. A., Bucks, C. M., Kane, C. M., Fallon, P. G., Pannell, R., et al. (2010) · Nature · doi:10.1038/nature08900 · Cited by 2,079
Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells
Moro, K., Yamada, T., Tanabe, M., Takeuchi, T., Ikawa, T., Kawamoto, H., Furusawa, J.-I., Ohtani, M., Fujii, H., & Koyasu, S. (2009) · Nature · doi:10.1038/nature08636 · Cited by 1,994
Snippert, H. J., van der Flier, L. G., Sato, T., van Es, J. H., van den Born, M., Kroon-Veenboer, C., Barker, N., Klein, A. M., van Rheenen, J., Simons, B. D., et al. (2010) · Cell · doi:10.1016/j.cell.2010.09.016 · Cited by 1,951
Microbiota-mediated colonization resistance against intestinal pathogens
Buffie, C. G., & Pamer, E. G. (2013) · Nature reviews. Immunology · doi:10.1038/nri3535 · Cited by 1,564
Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus
Monticelli, L. A., Sonnenberg, G. F., Abt, M. C., Alenghat, T., Ziegler, C. G. K., Doering, T. A., Angelosanto, J., Laidlaw, B. J., Yang, C. Y., Sathaliyawala, T., et al. (2011) · Nature Immunology · doi:10.1038/ni.2131 · Cited by 1,327
Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus
Monticelli (2011) · PubMed · doi:10.1031/ni.2131 · Cited by 1,286
Homeostatic Immunity and the Microbiota
Belkaid, Y., & Harrison, O. J. (2017) · Immunity · doi:10.1016/j.immuni.2017.04.008 · Cited by 1,261
Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit
von Moltke, J., Ji, M., Liang, H.-E., & Locksley, R. M. (2016) · Nature · doi:10.1038/nature16161 · Cited by 1,230
Self-citationThe maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring
Choi, G. B., Yim, Y. S., Wong, H., Kim, S., Kim, H., Kim, S. V., Hoeffer, C. A., Littman, D. R., & Huh, J. R. (2016) · Science · doi:10.1126/science.aad0314 · Cited by 1,214 · cited 1×
“Emerging roles for IL-17 family members in neural networks (Choi et al., 2016), including in nematodes (Chen et al.”
Systemically dispersed innate IL-13–expressing cells in type 2 immunity
Price, A. E., Liang, H.-E., Sullivan, B. M., Reinhardt, R. L., Eisley, C. J., Erle, D. J., & Locksley, R. M. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1003988107 · Cited by 1,134
Self-citationType 2 innate lymphoid cells control eosinophil homeostasis
Nussbaum, J. C., Dyken, S. J. V., von Moltke, J., Cheng, L. E., Mohapatra, A., Molofsky, A. B., Thornton, E. E., Krummel, M. F., Chawla, A., Liang, H.-E., et al. (2013) · Nature · doi:10.1038/nature12526 · Cited by 1,069
Self-citationIntestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites
Gerbe, F., Sidot, E., Smyth, D. J., Ohmoto, M., Matsumoto, I., Dardalhon, V., Cesses, P., Garnier, L., Pouzolles, M., Brulin, B., et al. (2016) · Nature · doi:10.1038/nature16527 · Cited by 1,002
Symbiotic digestion of lignocellulose in termite guts
Brune, A. (2014) · Nature Reviews Microbiology · doi:10.1038/nrmicro3182 · Cited by 973
Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut
Howitt, M. R., Lavoie, S., Michaud, M., Blum, A. M., Tran, S. V., Weinstock, J. V., Gallini, C. A., Redding, K., Margolskee, R. F., Osborne, L. C., et al. (2016) · Science · doi:10.1126/science.aaf1648 · Cited by 939
Specification of tissue-resident macrophages during organogenesis
Mass, E., Ballesteros, I., Farlik, M., Halbritter, F., Günther, P., Crozet, L., Jacome-Galarza, C. E., Händler, K., Klughammer, J., Kobayashi, Y., et al. (2016) · Science · doi:10.1126/science.aaf4238 · Cited by 891
Molofsky, A. B., Nussbaum, J. C., Liang, H.-E., Dyken, S. J. V., Cheng, L. E., Mohapatra, A., Chawla, A., & Locksley, R. M. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20121964 · Cited by 867
Self-citationBiochemistry and Evolution of Anaerobic Energy Metabolism in Eukaryotes
Müller, M., Mentel, M., van Hellemond, J. J., Henze, K., Woehle, C., Gould, S. B., Yu, R.-Y., van der Giezen, M., Tielens, A. G. M., & Martin, W. F. (2012) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.05024-11 · Cited by 838
IL-17 Signaling: The Yin and the Yang
Amatya, N., Garg, A. V., & Gaffen, S. L. (2017) · Trends in Immunology · doi:10.1016/j.it.2017.01.006 · Cited by 785
Fallon, P. G., Ballantyne, S. J., Mangan, N. E., Barlow, J. L., Dasvarma, A., Hewett, D. R., McIlgorm, A., Jolin, H. E., & McKenzie, A. N. J. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20051615 · Cited by 738
Gury-BenAri, M., Thaiss, C. A., Serafini, N., Winter, D. R., Giladi, A., Lara-Astiaso, D., Levy, M., Salame, T. M., Weiner, A., David, E., et al. (2016) · Cell · doi:10.1016/j.cell.2016.07.043 · Cited by 587
Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling
Hayakawa, Y., Sakitani, K., Konishi, M., Asfaha, S., Niikura, R., Tomita, H., Renz, B. W., Tailor, Y. H., Macchini, M., Middelhoff, M. A., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.11.005 · Cited by 577
Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity
Liang, H.-E., Reinhardt, R. L., Bando, J. K., Sullivan, B. M., Ho, I., & Locksley, R. M. (2011) · Nature Immunology · doi:10.1038/ni.2182 · Cited by 439
Self-citationTordesillas, L., Berin, M. C., & Sampson, H. A. (2017) · Immunity · doi:10.1016/j.immuni.2017.07.004 · Cited by 346
Host-Protozoan Interactions Protect from Mucosal Infections through Activation of the Inflammasome
Chudnovskiy, A., Mortha, A., Kana, V., Kennard, A., Ramirez, J. D., Rahman, A., Remark, R., Mogno, I., Ng, R., Gnjatic, S., et al. (2016) · Cell · doi:10.1016/j.cell.2016.08.076 · Cited by 325
Genetics and Pathogenesis of Inflammatory Bowel Disease
Liu, T.-C., & Stappenbeck, T. S. (2016) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-012615-044152 · Cited by 289
The Ubiquitin Modifying Enzyme A20 Restricts B Cell Survival and Prevents Autoimmunity
Tavares, R. M., Turer, E. E., Liu, C. L., Advincula, R., Scapini, P., Rhee, L., Barrera, J., Lowell, C. A., Utz, P. J., Malynn, B. A., et al. (2010) · Immunity · doi:10.1016/j.immuni.2010.07.017 · Cited by 270
Self-citationTrained Immunity: An Ancient Way of Remembering
Netea, M. G., & van der Meer, J. W. M. (2017) · Cell Host & Microbe · doi:10.1016/j.chom.2017.02.003 · Cited by 259
Van Dyken, S. J., Mohapatra, A., Nussbaum, J. C., Molofsky, A. B., Thornton, E. E., Ziegler, S. F., McKenzie, A. N. J., Krummel, M. F., Liang, H.-E., & Locksley, R. M. (2014) · Immunity · doi:10.1016/j.immuni.2014.02.003 · Cited by 251
Self-citationSnippert, H. J. G., Schepers, A. G., van Es, J. H., Simons, B. D., & Clevers, H. C. (2013) · EMBO Reports · doi:10.1002/embr.201337799 · Cited by 239
Smithers, S. R., & Terry, R. J. (1969) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1969.tb15904.x · Cited by 215
Amphiregulin, a T H 2 Cytokine Enhancing Resistance to Nematodes
Zaiss, D. M. W., Yang, L., Shah, P. R., Kobie, J. J., Urban, J. F., & Mosmann, T. R. (2006) · Science · doi:10.1126/science.1133715 · Cited by 195
Innate immunological function of TH2 cells in vivo
Guo, L., Huang, Y., Chen, X., Hu‐Li, J., Urban, J. F., & Paul, W. E. (2015) · Nature Immunology · doi:10.1038/ni.3244 · Cited by 193
Are Human Intestinal Eukaryotes Beneficial or Commensals?
Lukeš, J., Stensvold, C. R., Jirků‐Pomajbíková, K., & Parfrey, L. W. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1005039 · Cited by 192
Identification and distribution of developing innate lymphoid cells in the fetal mouse intestine
Bando, J. K., Liang, H.-E., & Locksley, R. M. (2014) · Nature Immunology · doi:10.1038/ni.3057 · Cited by 179
Self-citationInsight into SUCNR1 (GPR91) structure and function
Gilissen, J., Jouret, F., Pirotte, B., & Hanson, J. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.01.008 · Cited by 157
TRPM4 and TRPM5 are both required for normal signaling in taste receptor cells
Banik, D. D., Martin, L. E., Freichel, M., Torregrossa, A., & Medler, K. F. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1718802115 · Cited by 149
The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity
Song, X., He, X., Li, X., & Qian, Y. (2016) · Cellular and Molecular Immunology · doi:10.1038/cmi.2015.105 · Cited by 129
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Garg, A. V., Ahmed, M., Vallejo, A. N., Ma, A., & Gaffen, S. L. (2013) · Science Signaling · doi:10.1126/scisignal.2003699 · Cited by 128
Self-citationIL-17 is a neuromodulator of Caenorhabditis elegans sensory responses
Chen, C., Itakura, E., Nelson, G. M., Sheng, M., Laurent, P., Fenk, L. A., Butcher, R. A., Hegde, R. S., & de Bono, M. (2017) · Nature · doi:10.1038/nature20818 · Cited by 127
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Bando, J. K., Nussbaum, J. C., Liang, H.-E., & Locksley, R. M. (2013) · Journal of Leukocyte Biology · doi:10.1189/jlb.0213084 · Cited by 102
Self-citationImmunopathology of intestinal helminth infection
Garside, P., Kennedy, M. W., Wakelin, D., & Lawrence, C. E. (2000) · Parasite Immunology · doi:10.1046/j.1365-3024.2000.00344.x · Cited by 99
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Middelhoff, M. A., Westphalen, C. B., Hayakawa, Y., Yan, K. S., Gershon, M. D., Wang, T. C., & Quante, M. (2017) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00073.2017 · Cited by 97
Escalante, N. K., Lemire, P., Tleugabulova, M. C., Prescott, D., Mortha, A., Streutker, C., Girardin, S. E., Philpott, D. J., & Mallevaey, T. (2016) · The Journal of Experimental Medicine · doi:10.1084/jem.20161776 · Cited by 93
Sato, A. (2007) · Anatomical Science International · doi:10.1111/j.1447-073x.2007.00188.x · Cited by 88
Buckley, K. M., Ho, E. C. H., Hibino, T., Schrankel, C. S., Schuh, N. W., Wang, G., & Rast, J. P. (2017) · eLife · doi:10.7554/elife.23481 · Cited by 77
The Pathogenesis of Resection-Associated Intestinal Adaptation
Warner, B. W. (2016) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2016.05.001 · Cited by 72
Characterization of Lamprey IL-17 Family Members and Their Receptors
Han, Q., Das, S., Hirano, M., Holland, S. J., McCurley, N., Guo, P., Rosenberg, C. S., Boehm, T., & Cooper, M. D. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500892 · Cited by 60
I-L-C-2 it: type 2 immunity and group 2 innate lymphoid cells in homeostasis
von Moltke, J., & Locksley, R. (2014) · Current Opinion in Immunology · doi:10.1016/j.coi.2014.09.009 · Cited by 57
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RING, M. (1959) · Proceedings of the Zoological Society of London · doi:10.1111/j.1469-7998.1959.tb05528.x · Cited by 12
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Metadata
- Authors
- Schneider, C., O’Leary, C. E., von Moltke, J., Liang, H.-E., Ang, Q. Y., Turnbaugh, P. J., Radhakrishnan, S., Pellizzon, M., Ma, A., & Locksley, R. M.
- Affiliations
- University of California, San Francisco (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Locksley, Richard M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 174
- Issue
- 2
- Pages
- 271-284.e14
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6046262
- OpenAlex
- W2807333794
- Cited by
- 478
- References
- 54
- Citations by year
- 2026: 56 · 2025: 69 · 2024: 60 · 2023: 57 · 2022: 58 · 2021: 60 · 2020: 47 · 2019: 49 · 2018: 20
- FWCI
- 18.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH (AI26918, AI30663, HL128903, HL122593)
- Howard Hughes Medical Institute
- Sandler Asthma Basic Research Center at the UCSF
- Swiss National Science Foundation (P2EZP3_162266, P300PA_171591)
- Nadia’s Gift Foundation Innovator
- Damon Runyon Cancer Research Foundation (DRR-42-16)
- UCSF Program for Breakthrough Biomedical Research
- Sandler Foundation
- Searle Scholars Program (SSP-2016-1352)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Life Sciences › Immunology and Microbiology › Parasitology › Parasites and Host Interactions
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- tuft cells, ILC2, IL-25, A20, succinic acid, acetate, GPR91, TRPM5, Tritrichomonas, intestinal helminths, concomitant immunity, dietary polysaccharides, weaning
- MeSH terms
- Tumor Necrosis Factor alpha-Induced Protein 3, Acetates, Animals, Dietary Fiber, Energy Metabolism, Epithelial Cells, Interleukins, Intestinal Mucosa, Intestine, Small, Mice, Inbred C57BL, Mice, Transgenic, Plasmids, Tritrichomonas, Receptors, Interleukin, Succinic Acid, Receptors, G-Protein-Coupled, TRPM Cation Channels, Mice, Receptors, Interleukin-17, Microbiota
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