Epithelial Nlrp10 inflammasome mediates protection against intestinal autoinflammation

Danping Zheng; Gayatree Mohapatra; Lara Kern; Yiming He; Merav D Shmueli; Rafael Valdés-Mas; Aleksandra A Kolodziejczyk; Tomasz Próchnicki; Matilde B Vasconcelos; Lena Schorr; Franziska Hertel; Ye Seul Lee; Miguel Camacho Rufino; Emmanuelle Ceddaha; Sandy Shimshy; Ryan James Hodgetts; Mally Dori-Bachash; Christian Kleimeyer; Kim Goldenberg; Melina Heinemann; Noa Stettner; Alon Harmelin; Hagit Shapiro; Jens Puschhof; Minhu Chen; Richard A Flavell; Eicke Latz; Yifat Merbl; Suhaib K Abdeen; Eran Elinav

doi:10.1038/s41590-023-01450-z

Epithelial Nlrp10 inflammasome mediates protection against intestinal autoinflammation

Danping Zheng, Gayatree Mohapatra, Lara Kern, Yiming He, Merav D Shmueli, Rafael Valdés-Mas, Aleksandra A Kolodziejczyk, Tomasz Próchnicki, Matilde B Vasconcelos, Lena Schorr, Franziska Hertel, Ye Seul Lee, Miguel Camacho Rufino, Emmanuelle Ceddaha, Sandy Shimshy, Ryan James Hodgetts, Mally Dori-Bachash, Christian Kleimeyer, Kim Goldenberg, Melina HeinemannNoa Stettner, Alon Harmelin, Hagit Shapiro, Jens Puschhof, Minhu Chen, Richard A Flavell, Eicke Latz, Yifat Merbl, Suhaib K Abdeen^*, Eran Elinav^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

Abstract

The authors show that Nlrp10 can form a functional inflammasome in vitro and ex vivo, and that this inflammasome is protective in dextran sodium sulfate-induced colitis in mice.Unlike other nucleotide oligomerization domain-like receptors, Nlrp10 lacks a canonical leucine-rich repeat domain, suggesting that it is incapable of signal sensing and inflammasome formation. Here we show that mouse Nlrp10 is expressed in distal colonic intestinal epithelial cells (IECs) and modulated by the intestinal microbiome. In vitro, Nlrp10 forms an Apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)-dependent, m-3M3FBS-activated, polyinosinic:polycytidylic acid-modulated inflammasome driving interleukin-1 beta and interleukin-18 secretion. In vivo, Nlrp10 signaling is dispensable during steady state but becomes functional during autoinflammation in antagonizing mucosal damage. Importantly, whole-body or conditional IEC Nlrp10 depletion leads to reduced IEC caspase-1 activation, coupled with enhanced susceptibility to dextran sodium sulfate-induced colitis, mediated by altered inflammatory and healing programs. Collectively, understanding Nlrp10 inflammasome-dependent and independent activity, regulation and possible human relevance might facilitate the development of new innate immune anti-inflammatory interventions.

Original language	English
Pages (from-to)	585-594
Number of pages	10
Journal	Nature Immunology
Volume	24
Issue number	4
Early online date	20 Mar 2023
DOIs	https://doi.org/10.1038/s41590-023-01450-z
Publication status	Published - Apr 2023

Bibliographical note

We thank the members of the Elinav laboratory, Weizmann Institute of Science and members of the German Cancer Research Center Microbiome & Cancer division for insightful discussions; C. Bar-Nathan for dedicated GF mouse husbandry. D.Z. is the recipient of the European Crohn’s and Colitis Organization Fellowship and is supported by the Ke Lin Program of the First Affiliated Hospital, Sun Yat‐sen University. L.K. is funded by the postdoctoral Walter Benjamin fellowship from the German Research Foundation (no. 447836288). Y.H. is supported by the Ke Lin Program of the First Affiliated Hospital, Sun Yat‐sen University. M.S.D. is supported by the Marie Skłodowska-Curie Individual Fellowship (Horizon 2020 grant no. GAP-845066). R.V.-M. is the recipient of the Weizmann Institute ‘La Caixa’ Foundation Postdoctoral Fellowship. H.S. is an incumbent of the Vera Rosenberg Schwartz Research Fellow Chair. S.K.A. is supported by the Israeli Ministry of Science and Technology Zvi Yanai Fellowship. M.H. is funded by the German Research Foundation (no. 438122637). E.E. is supported by the Adelis Foundation, Pearl Welinsky Merlo Scientific Progress Research Fund, Park Avenue Charitable Fund, Hanna and Dr. Ludwik Wallach Cancer Research Fund, Daniel Morris Trust, Wolfson Family Charitable Trust and Wolfson Foundation, Ben B. and Joyce E. Eisenberg Foundation, White Rose International Foundation, Estate of Bernard Bishin for the WIS-Clalit Program, Else Kröener-Fresenius Foundation, Jeanne and Joseph Nissim Center for Life Sciences Research and by grants funded by the European Research Council, Israel Science Foundation, Israel Ministry of Science and Technology, Israel Ministry of Health, Helmholtz Foundation, Garvan Institute of Medical Research, European Crohn’s and Colitis Organization, Deutsch-Israelische Projektkooperation, Infectious Diseases Society of America Foundation and Wellcome Trust. E.E. is the incumbent of the Sir Marc and Lady Tania Feldmann Professorial Chair, a senior fellow of the Canadian Institute of Advanced Research and an international scholar of the Bill & Melinda Gates Foundation and Howard Hughes Medical Institute.

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology

Access to Document

10.1038/s41590-023-01450-z

Cite this

Zheng, D., Mohapatra, G., Kern, L., He, Y., Shmueli, M. D., Valdés-Mas, R., Kolodziejczyk, A. A., Próchnicki, T., Vasconcelos, M. B., Schorr, L., Hertel, F., Lee, Y. S., Rufino, M. C., Ceddaha, E., Shimshy, S., Hodgetts, R. J., Dori-Bachash, M., Kleimeyer, C., Goldenberg, K., ... Elinav, E. (2023). Epithelial Nlrp10 inflammasome mediates protection against intestinal autoinflammation. Nature Immunology, 24(4), 585-594. https://doi.org/10.1038/s41590-023-01450-z

@article{a6054d74d51f4e81936956f7d0097781,

title = "Epithelial Nlrp10 inflammasome mediates protection against intestinal autoinflammation",

abstract = "The authors show that Nlrp10 can form a functional inflammasome in vitro and ex vivo, and that this inflammasome is protective in dextran sodium sulfate-induced colitis in mice.Unlike other nucleotide oligomerization domain-like receptors, Nlrp10 lacks a canonical leucine-rich repeat domain, suggesting that it is incapable of signal sensing and inflammasome formation. Here we show that mouse Nlrp10 is expressed in distal colonic intestinal epithelial cells (IECs) and modulated by the intestinal microbiome. In vitro, Nlrp10 forms an Apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)-dependent, m-3M3FBS-activated, polyinosinic:polycytidylic acid-modulated inflammasome driving interleukin-1 beta and interleukin-18 secretion. In vivo, Nlrp10 signaling is dispensable during steady state but becomes functional during autoinflammation in antagonizing mucosal damage. Importantly, whole-body or conditional IEC Nlrp10 depletion leads to reduced IEC caspase-1 activation, coupled with enhanced susceptibility to dextran sodium sulfate-induced colitis, mediated by altered inflammatory and healing programs. Collectively, understanding Nlrp10 inflammasome-dependent and independent activity, regulation and possible human relevance might facilitate the development of new innate immune anti-inflammatory interventions.",

author = "Danping Zheng and Gayatree Mohapatra and Lara Kern and Yiming He and Shmueli, {Merav D} and Rafael Vald{\'e}s-Mas and Kolodziejczyk, {Aleksandra A} and Tomasz Pr{\'o}chnicki and Vasconcelos, {Matilde B} and Lena Schorr and Franziska Hertel and Lee, {Ye Seul} and Rufino, {Miguel Camacho} and Emmanuelle Ceddaha and Sandy Shimshy and Hodgetts, {Ryan James} and Mally Dori-Bachash and Christian Kleimeyer and Kim Goldenberg and Melina Heinemann and Noa Stettner and Alon Harmelin and Hagit Shapiro and Jens Puschhof and Minhu Chen and Flavell, {Richard A} and Eicke Latz and Yifat Merbl and Abdeen, {Suhaib K} and Eran Elinav",

note = "We thank the members of the Elinav laboratory, Weizmann Institute of Science and members of the German Cancer Research Center Microbiome & Cancer division for insightful discussions; C. Bar-Nathan for dedicated GF mouse husbandry. D.Z. is the recipient of the European Crohn{\textquoteright}s and Colitis Organization Fellowship and is supported by the Ke Lin Program of the First Affiliated Hospital, Sun Yat‐sen University. L.K. is funded by the postdoctoral Walter Benjamin fellowship from the German Research Foundation (no. 447836288). Y.H. is supported by the Ke Lin Program of the First Affiliated Hospital, Sun Yat‐sen University. M.S.D. is supported by the Marie Sk{\l}odowska-Curie Individual Fellowship (Horizon 2020 grant no. GAP-845066). R.V.-M. is the recipient of the Weizmann Institute {\textquoteleft}La Caixa{\textquoteright} Foundation Postdoctoral Fellowship. H.S. is an incumbent of the Vera Rosenberg Schwartz Research Fellow Chair. S.K.A. is supported by the Israeli Ministry of Science and Technology Zvi Yanai Fellowship. M.H. is funded by the German Research Foundation (no. 438122637). E.E. is supported by the Adelis Foundation, Pearl Welinsky Merlo Scientific Progress Research Fund, Park Avenue Charitable Fund, Hanna and Dr. Ludwik Wallach Cancer Research Fund, Daniel Morris Trust, Wolfson Family Charitable Trust and Wolfson Foundation, Ben B. and Joyce E. Eisenberg Foundation, White Rose International Foundation, Estate of Bernard Bishin for the WIS-Clalit Program, Else Kr{\"o}ener-Fresenius Foundation, Jeanne and Joseph Nissim Center for Life Sciences Research and by grants funded by the European Research Council, Israel Science Foundation, Israel Ministry of Science and Technology, Israel Ministry of Health, Helmholtz Foundation, Garvan Institute of Medical Research, European Crohn{\textquoteright}s and Colitis Organization, Deutsch-Israelische Projektkooperation, Infectious Diseases Society of America Foundation and Wellcome Trust. E.E. is the incumbent of the Sir Marc and Lady Tania Feldmann Professorial Chair, a senior fellow of the Canadian Institute of Advanced Research and an international scholar of the Bill & Melinda Gates Foundation and Howard Hughes Medical Institute.",

year = "2023",

month = apr,

doi = "10.1038/s41590-023-01450-z",

language = "English",

volume = "24",

pages = "585--594",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Publishing Group",

number = "4",

}

Zheng, D, Mohapatra, G , Kern, L, He, Y, Shmueli, MD, Valdés-Mas, R, Kolodziejczyk, AA, Próchnicki, T, Vasconcelos, MB, Schorr, L, Hertel, F, Lee, YS, Rufino, MC, Ceddaha, E, Shimshy, S, Hodgetts, RJ, Dori-Bachash, M, Kleimeyer, C, Goldenberg, K, Heinemann, M, Stettner, N, Harmelin, A , Shapiro, H, Puschhof, J, Chen, M, Flavell, RA, Latz, E, Merbl, Y , Abdeen, SK & Elinav, E 2023, 'Epithelial Nlrp10 inflammasome mediates protection against intestinal autoinflammation', Nature Immunology, vol. 24, no. 4, pp. 585-594. https://doi.org/10.1038/s41590-023-01450-z

TY - JOUR

T1 - Epithelial Nlrp10 inflammasome mediates protection against intestinal autoinflammation

AU - Zheng, Danping

AU - Mohapatra, Gayatree

AU - Kern, Lara

AU - He, Yiming

AU - Shmueli, Merav D

AU - Valdés-Mas, Rafael

AU - Kolodziejczyk, Aleksandra A

AU - Próchnicki, Tomasz

AU - Vasconcelos, Matilde B

AU - Schorr, Lena

AU - Hertel, Franziska

AU - Lee, Ye Seul

AU - Rufino, Miguel Camacho

AU - Ceddaha, Emmanuelle

AU - Shimshy, Sandy

AU - Hodgetts, Ryan James

AU - Dori-Bachash, Mally

AU - Kleimeyer, Christian

AU - Goldenberg, Kim

AU - Heinemann, Melina

AU - Stettner, Noa

AU - Harmelin, Alon

AU - Shapiro, Hagit

AU - Puschhof, Jens

AU - Chen, Minhu

AU - Flavell, Richard A

AU - Latz, Eicke

AU - Merbl, Yifat

AU - Abdeen, Suhaib K

AU - Elinav, Eran

N1 - We thank the members of the Elinav laboratory, Weizmann Institute of Science and members of the German Cancer Research Center Microbiome & Cancer division for insightful discussions; C. Bar-Nathan for dedicated GF mouse husbandry. D.Z. is the recipient of the European Crohn’s and Colitis Organization Fellowship and is supported by the Ke Lin Program of the First Affiliated Hospital, Sun Yat‐sen University. L.K. is funded by the postdoctoral Walter Benjamin fellowship from the German Research Foundation (no. 447836288). Y.H. is supported by the Ke Lin Program of the First Affiliated Hospital, Sun Yat‐sen University. M.S.D. is supported by the Marie Skłodowska-Curie Individual Fellowship (Horizon 2020 grant no. GAP-845066). R.V.-M. is the recipient of the Weizmann Institute ‘La Caixa’ Foundation Postdoctoral Fellowship. H.S. is an incumbent of the Vera Rosenberg Schwartz Research Fellow Chair. S.K.A. is supported by the Israeli Ministry of Science and Technology Zvi Yanai Fellowship. M.H. is funded by the German Research Foundation (no. 438122637). E.E. is supported by the Adelis Foundation, Pearl Welinsky Merlo Scientific Progress Research Fund, Park Avenue Charitable Fund, Hanna and Dr. Ludwik Wallach Cancer Research Fund, Daniel Morris Trust, Wolfson Family Charitable Trust and Wolfson Foundation, Ben B. and Joyce E. Eisenberg Foundation, White Rose International Foundation, Estate of Bernard Bishin for the WIS-Clalit Program, Else Kröener-Fresenius Foundation, Jeanne and Joseph Nissim Center for Life Sciences Research and by grants funded by the European Research Council, Israel Science Foundation, Israel Ministry of Science and Technology, Israel Ministry of Health, Helmholtz Foundation, Garvan Institute of Medical Research, European Crohn’s and Colitis Organization, Deutsch-Israelische Projektkooperation, Infectious Diseases Society of America Foundation and Wellcome Trust. E.E. is the incumbent of the Sir Marc and Lady Tania Feldmann Professorial Chair, a senior fellow of the Canadian Institute of Advanced Research and an international scholar of the Bill & Melinda Gates Foundation and Howard Hughes Medical Institute.

PY - 2023/4

Y1 - 2023/4

N2 - The authors show that Nlrp10 can form a functional inflammasome in vitro and ex vivo, and that this inflammasome is protective in dextran sodium sulfate-induced colitis in mice.Unlike other nucleotide oligomerization domain-like receptors, Nlrp10 lacks a canonical leucine-rich repeat domain, suggesting that it is incapable of signal sensing and inflammasome formation. Here we show that mouse Nlrp10 is expressed in distal colonic intestinal epithelial cells (IECs) and modulated by the intestinal microbiome. In vitro, Nlrp10 forms an Apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)-dependent, m-3M3FBS-activated, polyinosinic:polycytidylic acid-modulated inflammasome driving interleukin-1 beta and interleukin-18 secretion. In vivo, Nlrp10 signaling is dispensable during steady state but becomes functional during autoinflammation in antagonizing mucosal damage. Importantly, whole-body or conditional IEC Nlrp10 depletion leads to reduced IEC caspase-1 activation, coupled with enhanced susceptibility to dextran sodium sulfate-induced colitis, mediated by altered inflammatory and healing programs. Collectively, understanding Nlrp10 inflammasome-dependent and independent activity, regulation and possible human relevance might facilitate the development of new innate immune anti-inflammatory interventions.

AB - The authors show that Nlrp10 can form a functional inflammasome in vitro and ex vivo, and that this inflammasome is protective in dextran sodium sulfate-induced colitis in mice.Unlike other nucleotide oligomerization domain-like receptors, Nlrp10 lacks a canonical leucine-rich repeat domain, suggesting that it is incapable of signal sensing and inflammasome formation. Here we show that mouse Nlrp10 is expressed in distal colonic intestinal epithelial cells (IECs) and modulated by the intestinal microbiome. In vitro, Nlrp10 forms an Apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)-dependent, m-3M3FBS-activated, polyinosinic:polycytidylic acid-modulated inflammasome driving interleukin-1 beta and interleukin-18 secretion. In vivo, Nlrp10 signaling is dispensable during steady state but becomes functional during autoinflammation in antagonizing mucosal damage. Importantly, whole-body or conditional IEC Nlrp10 depletion leads to reduced IEC caspase-1 activation, coupled with enhanced susceptibility to dextran sodium sulfate-induced colitis, mediated by altered inflammatory and healing programs. Collectively, understanding Nlrp10 inflammasome-dependent and independent activity, regulation and possible human relevance might facilitate the development of new innate immune anti-inflammatory interventions.

UR - http://www.scopus.com/inward/record.url?scp=85150346360&partnerID=8YFLogxK

U2 - 10.1038/s41590-023-01450-z

DO - 10.1038/s41590-023-01450-z

M3 - Article

C2 - 36941399

SN - 1529-2908

VL - 24

SP - 585

EP - 594

JO - Nature Immunology

JF - Nature Immunology

IS - 4

ER -

Epithelial Nlrp10 inflammasome mediates protection against intestinal autoinflammation

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this