NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice

L. S. Tran; L. Ying; K. D’Costa; G. Wray-McCann; G. Kerr; L. Le; C. C. Allison; J. Ferrand; H. Chaudhry; J. Emery; A. De Paoli; N. Colon; S. Creed; M. Kaparakis-Liaskos; J. Como; J. K. Dowling; P. A. Johanesen; T. A. Kufer; J. S. Pedersen; A. Mansell; D. J. Philpott; K. D. Elgass; H. E. Abud; U. Nachbur; B. A. Croker; S. L. Masters; R. L. Ferrero

doi:10.1038/s41467-023-39487-1

NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice

L. S. Tran, L. Ying, K. D’Costa, G. Wray-McCann, G. Kerr, L. Le, C. C. Allison, J. Ferrand, H. Chaudhry, J. Emery, A. De Paoli, N. Colon, S. Creed, M. Kaparakis-Liaskos, J. Como, J. K. Dowling, P. A. Johanesen, T. A. Kufer, J. S. Pedersen, A. MansellD. J. Philpott, K. D. Elgass, H. E. Abud, U. Nachbur, B. A. Croker, S. L. Masters, R. L. Ferrero

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Abstract

The interleukin-1 family members, IL-1β and IL-18, are processed into their biologically active forms by multi-protein complexes, known as inflammasomes. Although the inflammasome pathways that mediate IL-1β processing in myeloid cells have been defined, those involved in IL-18 processing, particularly in non-myeloid cells, are still not well understood. Here we report that the host defence molecule NOD1 regulates IL-18 processing in mouse epithelial cells in response to the mucosal pathogen, Helicobacter pylori. Specifically, NOD1 in epithelial cells mediates IL-18 processing and maturation via interactions with caspase-1, instead of the canonical inflammasome pathway involving RIPK2, NF-κB, NLRP3 and ASC. NOD1 activation and IL-18 then help maintain epithelial homoeostasis to mediate protection against pre-neoplastic changes induced by gastric H. pylori infection in vivo. Our findings thus demonstrate a function for NOD1 in epithelial cell production of bioactive IL-18 and protection against H. pylori-induced pathology.

Original language	English
Article number	3804
Number of pages	18
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-39487-1
Publication status	Published - Dec 2023

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Tran, L. S., Ying, L., D’Costa, K., Wray-McCann, G., Kerr, G., Le, L., Allison, C. C., Ferrand, J., Chaudhry, H., Emery, J., De Paoli, A., Colon, N., Creed, S., Kaparakis-Liaskos, M., Como, J., Dowling, J. K., Johanesen, P. A., Kufer, T. A., Pedersen, J. S., ... Ferrero, R. L. (2023). NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice. Nature Communications, 14(1), Article 3804. https://doi.org/10.1038/s41467-023-39487-1

@article{c5cb6f7b014041e38770e276d43d8db5,

title = "NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice",

abstract = "The interleukin-1 family members, IL-1β and IL-18, are processed into their biologically active forms by multi-protein complexes, known as inflammasomes. Although the inflammasome pathways that mediate IL-1β processing in myeloid cells have been defined, those involved in IL-18 processing, particularly in non-myeloid cells, are still not well understood. Here we report that the host defence molecule NOD1 regulates IL-18 processing in mouse epithelial cells in response to the mucosal pathogen, Helicobacter pylori. Specifically, NOD1 in epithelial cells mediates IL-18 processing and maturation via interactions with caspase-1, instead of the canonical inflammasome pathway involving RIPK2, NF-κB, NLRP3 and ASC. NOD1 activation and IL-18 then help maintain epithelial homoeostasis to mediate protection against pre-neoplastic changes induced by gastric H. pylori infection in vivo. Our findings thus demonstrate a function for NOD1 in epithelial cell production of bioactive IL-18 and protection against H. pylori-induced pathology.",

author = "Tran, {L. S.} and L. Ying and K. D{\textquoteright}Costa and G. Wray-McCann and G. Kerr and L. Le and Allison, {C. C.} and J. Ferrand and H. Chaudhry and J. Emery and {De Paoli}, A. and N. Colon and S. Creed and M. Kaparakis-Liaskos and J. Como and Dowling, {J. K.} and Johanesen, {P. A.} and Kufer, {T. A.} and Pedersen, {J. S.} and A. Mansell and Philpott, {D. J.} and Elgass, {K. D.} and Abud, {H. E.} and U. Nachbur and Croker, {B. A.} and Masters, {S. L.} and Ferrero, {R. L.}",

note = "Funding Information: The authors thank L. Inglis and L. Scott (WEHI) for animal husbandry; W. Carter (WEHI) for assistance with biosafety compliance; Associate Prof. S. Bedoui (The University of Melbourne) for supplying the Nlrc4−/−mice; Mr. Dirk Truman (Monash Gene Targeting Facility, Monash University) for designing the Nod1 targeting strategy and generating the heterozygote animals; and Drs. F. Cribbin and R. Smith (Hudson Institute) for expert editorial assistance with the manuscript. The authors acknowledge assistance from the Monash BDI Organoid Programme, Monash Biomedicine Discovery Institute (Victoria, Australia) and the Monash Micro Imaging platform at MHTP (MMI-MHTP) for access and assistance with microscopy and analysis. The research in R.L.F.{\textquoteright}s laboratory was supported by project grants (APP1030243 to R.L.F. and B.A.C.; APP1107930) and Senior Research Fellowships (APP1079904, 606476), from the National Health and Medical Research Council of Australia, and the Outside Study Programme (Monash University). This work was supported by the German Academic Exchange Service (DAAD), grant PPP #57654618, to R.L.F. and T.A.K. The generation of the Nod1fl/flmice was funded by the Public Health Agency of Canada (to D.J.P., R.L.F.). L.Y. was supported by funding from the U.S. Department of Defense (Award No. W81XWH-17-1-0606). Research at the Hudson Institute of Medical Research is supported by the Victorian Government{\textquoteright}s Operational Infrastructure Support Programme. Funding Information: The authors thank L. Inglis and L. Scott (WEHI) for animal husbandry; W. Carter (WEHI) for assistance with biosafety compliance; Associate Prof. S. Bedoui (The University of Melbourne) for supplying the Nlrc4 mice; Mr. Dirk Truman (Monash Gene Targeting Facility, Monash University) for designing the Nod1 targeting strategy and generating the heterozygote animals; and Drs. F. Cribbin and R. Smith (Hudson Institute) for expert editorial assistance with the manuscript. The authors acknowledge assistance from the Monash BDI Organoid Programme, Monash Biomedicine Discovery Institute (Victoria, Australia) and the Monash Micro Imaging platform at MHTP (MMI-MHTP) for access and assistance with microscopy and analysis. The research in R.L.F.{\textquoteright}s laboratory was supported by project grants (APP1030243 to R.L.F. and B.A.C.; APP1107930) and Senior Research Fellowships (APP1079904, 606476), from the National Health and Medical Research Council of Australia, and the Outside Study Programme (Monash University). This work was supported by the German Academic Exchange Service (DAAD), grant PPP #57654618, to R.L.F. and T.A.K. The generation of the Nod1 mice was funded by the Public Health Agency of Canada (to D.J.P., R.L.F.). L.Y. was supported by funding from the U.S. Department of Defense (Award No. W81XWH-17-1-0606). Research at the Hudson Institute of Medical Research is supported by the Victorian Government{\textquoteright}s Operational Infrastructure Support Programme. −/− fl/fl Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-39487-1",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Tran, LS, Ying, L, D’Costa, K, Wray-McCann, G, Kerr, G, Le, L, Allison, CC, Ferrand, J, Chaudhry, H, Emery, J, De Paoli, A, Colon, N, Creed, S, Kaparakis-Liaskos, M, Como, J, Dowling, JK, Johanesen, PA, Kufer, TA, Pedersen, JS, Mansell, A, Philpott, DJ, Elgass, KD, Abud, HE, Nachbur, U, Croker, BA, Masters, SL & Ferrero, RL 2023, 'NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice', Nature Communications, vol. 14, no. 1, 3804. https://doi.org/10.1038/s41467-023-39487-1

TY - JOUR

T1 - NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice

AU - Tran, L. S.

AU - Ying, L.

AU - D’Costa, K.

AU - Wray-McCann, G.

AU - Kerr, G.

AU - Le, L.

AU - Allison, C. C.

AU - Ferrand, J.

AU - Chaudhry, H.

AU - Emery, J.

AU - De Paoli, A.

AU - Colon, N.

AU - Creed, S.

AU - Kaparakis-Liaskos, M.

AU - Como, J.

AU - Dowling, J. K.

AU - Johanesen, P. A.

AU - Kufer, T. A.

AU - Pedersen, J. S.

AU - Mansell, A.

AU - Philpott, D. J.

AU - Elgass, K. D.

AU - Abud, H. E.

AU - Nachbur, U.

AU - Croker, B. A.

AU - Masters, S. L.

AU - Ferrero, R. L.

N1 - Funding Information: The authors thank L. Inglis and L. Scott (WEHI) for animal husbandry; W. Carter (WEHI) for assistance with biosafety compliance; Associate Prof. S. Bedoui (The University of Melbourne) for supplying the Nlrc4−/−mice; Mr. Dirk Truman (Monash Gene Targeting Facility, Monash University) for designing the Nod1 targeting strategy and generating the heterozygote animals; and Drs. F. Cribbin and R. Smith (Hudson Institute) for expert editorial assistance with the manuscript. The authors acknowledge assistance from the Monash BDI Organoid Programme, Monash Biomedicine Discovery Institute (Victoria, Australia) and the Monash Micro Imaging platform at MHTP (MMI-MHTP) for access and assistance with microscopy and analysis. The research in R.L.F.’s laboratory was supported by project grants (APP1030243 to R.L.F. and B.A.C.; APP1107930) and Senior Research Fellowships (APP1079904, 606476), from the National Health and Medical Research Council of Australia, and the Outside Study Programme (Monash University). This work was supported by the German Academic Exchange Service (DAAD), grant PPP #57654618, to R.L.F. and T.A.K. The generation of the Nod1fl/flmice was funded by the Public Health Agency of Canada (to D.J.P., R.L.F.). L.Y. was supported by funding from the U.S. Department of Defense (Award No. W81XWH-17-1-0606). Research at the Hudson Institute of Medical Research is supported by the Victorian Government’s Operational Infrastructure Support Programme. Funding Information: The authors thank L. Inglis and L. Scott (WEHI) for animal husbandry; W. Carter (WEHI) for assistance with biosafety compliance; Associate Prof. S. Bedoui (The University of Melbourne) for supplying the Nlrc4 mice; Mr. Dirk Truman (Monash Gene Targeting Facility, Monash University) for designing the Nod1 targeting strategy and generating the heterozygote animals; and Drs. F. Cribbin and R. Smith (Hudson Institute) for expert editorial assistance with the manuscript. The authors acknowledge assistance from the Monash BDI Organoid Programme, Monash Biomedicine Discovery Institute (Victoria, Australia) and the Monash Micro Imaging platform at MHTP (MMI-MHTP) for access and assistance with microscopy and analysis. The research in R.L.F.’s laboratory was supported by project grants (APP1030243 to R.L.F. and B.A.C.; APP1107930) and Senior Research Fellowships (APP1079904, 606476), from the National Health and Medical Research Council of Australia, and the Outside Study Programme (Monash University). This work was supported by the German Academic Exchange Service (DAAD), grant PPP #57654618, to R.L.F. and T.A.K. The generation of the Nod1 mice was funded by the Public Health Agency of Canada (to D.J.P., R.L.F.). L.Y. was supported by funding from the U.S. Department of Defense (Award No. W81XWH-17-1-0606). Research at the Hudson Institute of Medical Research is supported by the Victorian Government’s Operational Infrastructure Support Programme. −/− fl/fl Publisher Copyright: © 2023, The Author(s).

PY - 2023/12

Y1 - 2023/12

N2 - The interleukin-1 family members, IL-1β and IL-18, are processed into their biologically active forms by multi-protein complexes, known as inflammasomes. Although the inflammasome pathways that mediate IL-1β processing in myeloid cells have been defined, those involved in IL-18 processing, particularly in non-myeloid cells, are still not well understood. Here we report that the host defence molecule NOD1 regulates IL-18 processing in mouse epithelial cells in response to the mucosal pathogen, Helicobacter pylori. Specifically, NOD1 in epithelial cells mediates IL-18 processing and maturation via interactions with caspase-1, instead of the canonical inflammasome pathway involving RIPK2, NF-κB, NLRP3 and ASC. NOD1 activation and IL-18 then help maintain epithelial homoeostasis to mediate protection against pre-neoplastic changes induced by gastric H. pylori infection in vivo. Our findings thus demonstrate a function for NOD1 in epithelial cell production of bioactive IL-18 and protection against H. pylori-induced pathology.

AB - The interleukin-1 family members, IL-1β and IL-18, are processed into their biologically active forms by multi-protein complexes, known as inflammasomes. Although the inflammasome pathways that mediate IL-1β processing in myeloid cells have been defined, those involved in IL-18 processing, particularly in non-myeloid cells, are still not well understood. Here we report that the host defence molecule NOD1 regulates IL-18 processing in mouse epithelial cells in response to the mucosal pathogen, Helicobacter pylori. Specifically, NOD1 in epithelial cells mediates IL-18 processing and maturation via interactions with caspase-1, instead of the canonical inflammasome pathway involving RIPK2, NF-κB, NLRP3 and ASC. NOD1 activation and IL-18 then help maintain epithelial homoeostasis to mediate protection against pre-neoplastic changes induced by gastric H. pylori infection in vivo. Our findings thus demonstrate a function for NOD1 in epithelial cell production of bioactive IL-18 and protection against H. pylori-induced pathology.

UR - http://www.scopus.com/inward/record.url?scp=85163405469&partnerID=8YFLogxK

U2 - 10.1038/s41467-023-39487-1

DO - 10.1038/s41467-023-39487-1

M3 - Article

C2 - 37365163

AN - SCOPUS:85163405469

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3804

ER -

NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice

Abstract

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NLRC5, a new regulator of Helicobacter-induced inflammation

Helicobacter pylori acquisition of host cholesterol: its role in inflammation

NHMRC Research Fellowship

MHTP Medical Genomics Facility

Monash Micro Imaging

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NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice

Abstract

Access to Document

Other files and links

Projects

NLRC5, a new regulator of Helicobacter-induced inflammation

Helicobacter pylori acquisition of host cholesterol: its role in inflammation

NHMRC Research Fellowship

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MHTP Medical Genomics Facility

Monash Micro Imaging

Cite this