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Cited by 112Antifungal resistance and susceptibilityNeutrophil, Myeloperoxidase and Oxidative MechanismsFungal and yeast genetics research

IL-1 Coordinates the Neutrophil Response to C. albicans in the Oral Mucosa

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Altmeier, Simon, Toska, Albulena, Sparber, Florian, Teijeira, Alvaro, Halin, Cornelia, LeibundGut-Landmann, Salomé·2016·PLOS Pathogens
DOI 10.1371/journal.ppat.1005882PMC PMC5025078
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Abstract

Mucosal infections with Candida albicans belong to the most frequent forms of fungal diseases. Host protection is conferred by cellular immunity; however, the induction of antifungal immunity is not well understood. Using a mouse model of oropharyngeal candidiasis (OPC) we show that interleukin-1 receptor (IL-1R) signaling is critical for fungal control at the onset of infection through its impact on neutrophils at two levels. We demonstrate that both the recruitment of circulating neutrophils to the site of infection and the mobilization of newly generated neutrophils from the bone marrow depended on IL-1R. Consistently, IL-1R-deficient mice displayed impaired chemokine production at the site of infection and defective secretion of granulocyte colony-stimulating factor (G-CSF) in the circulation in response to C. albicans. Strikingly, endothelial cells were identified as the primary cellular source of G-CSF during OPC, which responded to IL-1α that was released from keratinocytes in the infected tissue. The IL-1-dependent crosstalk between two different cellular subsets of the nonhematopoietic compartment was confirmed in vitro using a novel murine tongue-derived keratinocyte cell line and an established endothelial cell line. These data establish a new link between IL-1 and granulopoiesis in the context of fungal infection. Together, we identified two complementary mechanisms coordinating the neutrophil response in the oral mucosa, which is critical for preventing fungal growth and dissemination, and thus protects the host from disease.

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Crossref · 10.1371/journal.ppat.1005882

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  • IL-1R signaling is critical for neutrophil function.

    “IL-1R signaling is critical for neutrophil function [26, 31, 32]”

    From Single-cell transcriptomics unveils skin cell specific antifungal immune responses and IL-1Ra- IL-1R immune evasion strategies of emerging fungal pathogen Candida auris (2024) · cites this paper as [31]

    The Results section on neutrophil recruitment (page unavailable) says IL-1R signaling was critical for the neutrophil response during oropharyngeal candidiasis in mice. The Discussion (page unavailable) specifies that the demonstrated effects concern neutrophil recruitment and production; it does not establish that IL-1R signaling is critical for neutrophil function generally or for neutrophils’ intrinsic activity. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • IL-1R signaling is critical for neutrophil recruitment and function and plays an important role in host defense against C. albicans in oral mucosa and systemic infection.

    “IL-1R signaling is critical for neutrophil recruitment and function and plays an important role in the host defense against C. albicans in oral mucosa and systemic infection [31, 32]”

    From Single-cell transcriptomics unveils skin cell specific antifungal immune responses and IL-1Ra- IL-1R immune evasion strategies of emerging fungal pathogen Candida auris (2024) · cites this paper as [31]

    The Results and Discussion show that IL-1R signaling promotes neutrophil recruitment and fungal control in a mouse model of oral candidiasis. The Discussion also reports previous evidence for an IL-1R role in systemic candidiasis, but this paper does not establish that IL-1R regulates neutrophil function during systemic infection; it says the protective mechanism was not addressed in most of those studies. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 48

  1. [1]Romani L. Immunity to fungal infections. Nature reviews. Immunology. 2011; 11: 275– 288. 10.1038/nri2939 21394104 · DOI · Paper page
  2. [2]Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC. Hidden killers. human fungal infections. Science translational medicine. 2012; 4: 165rv13 10.1126/scitranslmed.3004404 23253612 · DOI · Paper page
  3. [4]Pappu R, Rutz S, Ouyang W. Regulation of epithelial immunity by IL-17 family cytokines. Trends in immunology. 2012; 33: 343– 349. 10.1016/j.it.2012.02.008 22476048 · DOI
  4. [5]Sparber F, LeibundGut-Landmann S. Interleukin 17-Mediated Host Defense against Candida albicans. Pathogens. 2015; 4: 606– 619. 10.3390/pathogens4030606 26274976 PMC4584276 · DOI
  5. [6]Trautwein-Weidner K, Gladiator A, Nur S, Diethelm P, LeibundGut-Landmann S. IL-17-mediated antifungal defense in the oral mucosa is independent of neutrophils. Mucosal immunology. 2015; 8: 221– 231. 10.1038/mi.2014.57 25005360 · DOI
  6. [7]Huppler AR, Conti HR, Hernandez-Santos N, Darville T, Biswas PS, Gaffen SL. Role of neutrophils in IL-17-dependent immunity to mucosal candidiasis. Journal of immunology. 2014; 192: 1745– 1752. 10.4049/jimmunol.1302265 PMC3946223 24442441 · DOI
  7. [8]Pankhurst CL. Candidiasis (oropharyngeal). BMJ Clin Evid. 2009; 2009. PMC2907793 19445752
  8. [9]Lortholary O, Dupont B. Antifungal prophylaxis during neutropenia and immunodeficiency. Clin Microbiol Rev. 1997; 10: 477– 504. 9227863 PMC172931
  9. [10]Lieschke GJ, Grail D, Hodgson G, Metcalf D, Stanley E, Cheers C, et al Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood. 1994; 84: 1737– 1746. 7521686
  10. [11]Takizawa H, Boettcher S, Manz MG. Demand-adapted regulation of early hematopoiesis in infection and inflammation. Blood. 2012; 119: 2991– 3002. 10.1182/blood-2011-12-380113 22246037 · DOI
  11. [12]Kim ND, Luster AD. The role of tissue resident cells in neutrophil recruitment. Trends Immunol. 2015; 36: 547– 555. 10.1016/j.it.2015.07.007 26297103 PMC4567503 · DOI
  12. [13]Lanternier F, Cypowyj S, Picard C, Bustamante J, Lortholary O, Casanova J, et al Primary immunodeficiencies underlying fungal infections. Curr. Opin. Pediatr. 2013; 25: 736– 747. 10.1097/MOP.0000000000000031 24240293 PMC4098727 · DOI
  13. [15]Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Schwarzenberger P, et al Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. The Journal of experimental medicine. 2001; 194: 519– 527. 11514607 PMC2193502
  14. [17]Cho JS, Pietras EM, Garcia NC, Ramos RI, Farzam DM, Monroe HR, et al IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice. The Journal of clinical investigation. 2010; 120: 1762– 1773. 10.1172/JCI40891 20364087 PMC2860944 · DOI · Paper page
  15. [18]Umemura M, Yahagi A, Hamada S, Begum MD, Watanabe H, Kawakami K, et al IL-17-mediated regulation of innate and acquired immune response against pulmonary Mycobacterium bovis bacille Calmette-Guerin infection. Journal of immunology. 2007; 178: 3786– 3796. 17339477
  16. [19]Yuan S, Zhang S, Zhuang Y, Zhang H, Bai J, Hou Q. Interleukin-17 Stimulates STAT3-Mediated Endothelial Cell Activation for Neutrophil Recruitment. Cell Physiol Biochem. 2015; 36: 2340– 2356. 10.1159/000430197 26279438 · DOI
  17. [20]Gross O, Yazdi AS, Thomas CJ, Masin M, Heinz LX, Guarda G, et al Inflammasome activators induce interleukin-1α secretion via distinct pathways with differential requirement for the protease function of caspase-1. Immunity. 2012; 36: 388– 400. 10.1016/j.immuni.2012.01.018 22444631 · DOI
  18. [22]Gross O, Poeck H, Bscheider M, Dostert C, Hannesschlager N, Endres S, et al Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature. 2009; 459: 433– 436. 10.1038/nature07965 19339971 · DOI
  19. [23]van de Veerdonk, Frank L, Joosten LAB, Devesa I, Mora-Montes HM, Kanneganti T, Dinarello CA, et al Bypassing pathogen-induced inflammasome activation for the regulation of interleukin-1beta production by the fungal pathogen Candida albicans. J Infect Dis. 2009; 199: 1087– 1096. 10.1086/597274 19222370 · DOI
  20. [24]Vonk AG, Netea MG, van Krieken JH, Iwakura Y, van der Meer, Jos W M, Kullberg BJ. Endogenous interleukin (IL)-1 alpha and IL-1 beta are crucial for host defense against disseminated candidiasis. J Infect Dis. 2006; 193: 1419– 1426. 10.1086/503363 16619190 · DOI
  21. [25]Schaller M, Korting HC, Borelli C, Hamm G, Hube B. Candida albicans-secreted aspartic proteinases modify the epithelial cytokine response in an in vitro model of vaginal candidiasis. Infect Immun. 2005; 73: 2758– 2765. 10.1128/IAI.73.5.2758–2765.2005 15845479 PMC1087327 · DOI
  22. [26]Moyes DL, Runglall M, Murciano C, Shen C, Nayar D, Thavaraj S, et al A biphasic innate immune MAPK response discriminates between the yeast and hyphal forms of Candida albicans in epithelial cells. Cell host & microbe. 2010; 8: 225– 235. 10.1016/j.chom.2010.08.002 20833374 PMC2991069 · DOI
  23. [27]Steele C, Fidel PL. Cytokine and chemokine production by human oral and vaginal epithelial cells in response to Candida albicans. Infect Immun. 2002; 70: 577– 583. 11796585 PMC127706
  24. [29]Tomalka J, Ganesan S, Azodi E, Patel K, Majmudar P, Hall BA, et al A novel role for the NLRC4 inflammasome in mucosal defenses against the fungal pathogen Candida albicans. PLoS pathogens. 2011; 7: e1002379 10.1371/journal.ppat.1002379 22174673 PMC3234225 · DOI
  25. [30]Nitschké M, Aebischer D, Abadier M, Haener S, Lucic M, Vigl B, et al Differential requirement for ROCK in dendritic cell migration within lymphatic capillaries in steady-state and inflammation. Blood. 2012; 120: 2249– 2258. 10.1182/blood-2012-03-417923 22855606 · DOI
  26. [31]Lenhoff S, Olofsson T. Cytokine regulation of GM-CSF and G-CSF secretion by human umbilical cord vein endothelial cells (HUVEC). Cytokine. 1996; 8: 702– 709. 10.1006/cyto.1996.0093 8932981 · DOI
  27. [32]Presland RB, Dale BA. Epithelial structural proteins of the skin and oral cavity: function in health and disease. Crit Rev Oral Biol Med. 2000; 11: 383– 408. 11132762
  28. [33]Arbiser JL, Moses MA, Fernandez CA, Ghiso N, Cao Y, Klauber N, et al Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathways. Proc Natl Acad Sci U S A. 1997; 94: 861– 866. 9023347 PMC19604
  29. [34]Hise AG, Tomalka J, Ganesan S, Patel K, Hall BA, Brown GD, et al An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans. Cell host & microbe. 2009; 5: 487– 497. 10.1016/j.chom.2009.05.002 19454352 PMC2824856 · DOI
  30. [35]Leal S. M. Jr., Cowden S, Hsia YC, Ghannoum MA, Momany M, Pearlman E. Distinct roles for Dectin-1 and TLR4 in the pathogenesis of Aspergillus fumigatus keratitis. PLoS pathogens. 2010; 6: e1000976 10.1371/journal.ppat.1000976 20617171 PMC2895653 · DOI
  31. [37]Olaru F, Jensen LE. Staphylococcus aureus stimulates neutrophil targeting chemokine expression in keratinocytes through an autocrine IL-1alpha signaling loop. J Invest Dermatol. 2010; 130: 1866– 1876. 10.1038/jid.2010.37 20182449 PMC2886182 · DOI
  32. [38]Boettcher S, Gerosa RC, Radpour R, Bauer J, Ampenberger F, Heikenwalder M, et al Endothelial cells translate pathogen signals into G-CSF-driven emergency granulopoiesis. Blood. 2014; 124: 1393– 1403. 10.1182/blood-2014-04-570762 24990886 PMC4148762 · DOI
  33. [39]Barnes G, Pathak A, Schwartzberg L. G-CSF utilization rate and prescribing patterns in United States: associations between physician and patient factors and GCSF use. Cancer Med. 2014; 3: 1477– 1484. 10.1002/cam4.344 25410813 PMC4298373 · DOI
  34. [40]Wildbaum G, Shahar E, Katz R, Karin N, Etzioni A, Pollack S. Continuous G-CSF therapy for isolated chronic mucocutaneous candidiasis: complete clinical remission with restoration of IL-17 secretion. J Allergy Clin Immunol. 2013; 132: 761– 764. 10.1016/j.jaci.2013.04.018 23791509 · DOI
  35. [41]Lawlor KE, Campbell IK, Metcalf D, O'Donnell K, van Nieuwenhuijze A, Roberts AW, et al Critical role for granulocyte colony-stimulating factor in inflammatory arthritis. Proc Natl Acad Sci U S A. 2004; 101: 11398– 11403. 10.1073/pnas.0404328101 15272075 PMC509212 · DOI
  36. [42]Eyles JL, Hickey MJ, Norman MU, Croker BA, Roberts AW, Drake SF, et al A key role for G-CSF-induced neutrophil production and trafficking during inflammatory arthritis. Blood. 2008; 112: 5193– 5201. 10.1182/blood-2008-02-139535 18824600 · DOI
  37. [43]Mössner R, Beckmann I, Hallermann C, Neumann C, Reich K. Granulocyte colony-stimulating-factor-induced psoriasiform dermatitis resembles psoriasis with regard to abnormal cytokine expression and epidermal activation. Exp Dermatol. 2004; 13: 340– 346. 10.1111/j.0906-6705.2004.00190.x 15186319 · DOI
  38. [44]Cornish AL, Campbell IK, McKenzie BS, Chatfield S, Wicks IP. G-CSF and GM-CSF as therapeutic targets in rheumatoid arthritis. Nat Rev Rheumatol. 2009; 5: 554– 559. 10.1038/nrrheum.2009.178 19798030 · DOI
  39. [45]Bruno VM, Shetty AC, Yano J, Fidel PL, Noverr MC, Peters BM. Transcriptomic analysis of vulvovaginal candidiasis identifies a role for the NLRP3 inflammasome. MBio. 2015; 6 10.1128/mBio.00182-15 PMC4453569 25900651 · DOI · Paper page
  40. [46]Dongari-bagtzoglou A, Kashleva H, Villar CC. Bioactive interleukin-1alpha is cytolytically released from Candida albicans-infected oral epithelial cells. Med Mycol. 2004; 42: 531– 541. 15682642
  41. [47]Moyes DL, Wilson D, Richardson JP, Mogavero S, Tang SX, Wernecke J, et al Candidalysin is a fungal peptide toxin critical for mucosal infection. Nature. 2016; 532: 64– 68. 10.1038/nature17625 27027296 PMC4851236 · DOI
  42. [48]Horai R, Asano M, Sudo K, Kanuka H, Suzuki M, Nishihara M, et al Production of mice deficient in genes for interleukin (IL)-1alpha, IL-1beta, IL-1alpha/beta, and IL-1 receptor antagonist shows that IL-1beta is crucial in turpentine-induced fever development and glucocorticoid secretion. J Exp Med. 1998; 187: 1463– 1475. 9565638 PMC2212263
  43. [49]Labow M, Shuster D, Zetterstrom M, Nunes P, Terry R, Cullinan EB, et al Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice. Journal of immunology. 1997; 159: 2452– 2461. 9278338
  44. [50]Marino MW, Dunn A, Grail D, Inglese M, Noguchi Y, Richards E, et al Characterization of tumor necrosis factor-deficient mice. Proc Natl Acad Sci U S A. 1997; 94: 8093– 8098. 9223320 PMC21562
  45. [51]Zheng X, Wang Y, Wang Y. Hgc1, a novel hypha-specific G1 cyclin-related protein regulates Candida albicans hyphal morphogenesis. EMBO J. 2004; 23: 1845– 1856. 10.1038/sj.emboj.7600195 15071502 PMC394249 · DOI
  46. [52]Barelle CJ, Manson CL, MacCallum DM, Odds FC, Gow NA, Brown AJ. GFP as a quantitative reporter of gene regulation in Candida albicans. Yeast. 2004; 21: 333– 340. 10.1002/yea.1099 15042593 · DOI
  47. [53]Solis NV, Filler SG. Mouse model of oropharyngeal candidiasis. Nature protocols. 2012; 7: 637– 642. 10.1038/nprot.2012.011 22402633 PMC3671943 · DOI
  48. [54]Meyer M, Müller A, Yang J, Moik D, Ponzio G, Ornitz DM, et al FGF receptors 1 and 2 are key regulators of keratinocyte migration in vitro and in wounded skin. J Cell Sci. 2012; 125: 5690– 5701. 10.1242/jcs.108167 22992463 PMC3575704 · DOI

Cited by

Sorted by citations

Authors
Altmeier, S., Toska, A., Sparber, F., Teijeira, A., Halin, C., & LeibundGut-Landmann, S.
Affiliations
  • University of Zurich (CH)
  • ETH Zurich (CH)
ORCID
Venue
PLOS Pathogens
Publisher
Public Library of Science (PLoS)
Published
2016-09-15
Volume
12
Issue
9
Pages
e1005882
ISSN
  • 1553-7366 (ISSN-L)
  • 1553-7374
DOI
10.1371/journal.ppat.1005882
PMC
PMC5025078
OpenAlex
W2519902791
Cited by
112
References
6
Citations by year
2026: 5 · 2025: 7 · 2024: 10 · 2023: 6 · 2022: 13 · 2021: 12 · 2020: 18 · 2019: 10 · 2018: 19 · 2017: 11
FWCI
12.31
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Pathogens (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • ETH Zürich Research Collection (cc-by)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (PP00P3_150758, CRSII3_141848)
  • Austrian Science Fund (J3566)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords
interleukin-1 receptor signaling, Candida albicans, oropharyngeal candidiasis, neutrophils, neutrophil recruitment, granulopoiesis, granulocyte colony-stimulating factor, endothelial cells, keratinocytes, chemokine production, antifungal immunity, oral mucosa, host defense against fungi
MeSH terms
Animals, Candida albicans, Candidiasis, Mouth Mucosa, Neutrophils, Tongue, Keratinocytes, Granulocyte Colony-Stimulating Factor, Receptors, Interleukin-1, Mice, Knockout, Myelopoiesis, Endothelial Cells, Mice, Interleukin-1alpha

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