Epithelial endoplasmic reticulum stress orchestrates a protective IgA response

Joep Grootjans; Niklas Krupka; Shuhei Hosomi; Juan D Matute; Thomas Hanley; Svetlana Saveljeva; Thomas Gensollen; Jarom Heijmans; Hai Li; Julien P Limenitakis; Stephanie C Ganal-Vonarburg; Shengbao Suo; Adrienne M Luoma; Yosuke Shimodaira; Jinzhi Duan; David Q Shih; Margaret E Conner; Jonathan N Glickman; Gwenny M Fuhler; Noah W Palm; Marcel R de Zoete; C Janneke van der Woude; Guo-Cheng Yuan; Kai W Wucherpfennig; Stephan R Targan; Philip Rosenstiel; Richard A Flavell; Kathy D McCoy; Andrew J Macpherson; Arthur Kaser; Richard S Blumberg

doi:10.1126/science.aat7186

Epithelial endoplasmic reticulum stress orchestrates a protective IgA response

Joep Grootjans
, Niklas Krupka
, Shuhei Hosomi
, Juan D Matute
, Thomas Hanley
, Svetlana Saveljeva
, Thomas Gensollen
, Jarom Heijmans
, Hai Li
, Julien P Limenitakis
, Stephanie C Ganal-Vonarburg
, Shengbao Suo
, Adrienne M Luoma
, Yosuke Shimodaira
, Jinzhi Duan
, David Q Shih
, Margaret E Conner
, Jonathan N Glickman
, Gwenny M Fuhler
, Noah W Palm

Marcel R de Zoete, C Janneke van der Woude, Guo-Cheng Yuan, Kai W Wucherpfennig, Stephan R Targan, Philip Rosenstiel, Richard A Flavell, Kathy D McCoy, Andrew J Macpherson, Arthur Kaser, Richard S Blumberg

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

Abstract

Immunoglobulin A (IgA) is the major secretory immunoglobulin isotype found at mucosal surfaces, where it regulates microbial commensalism and excludes luminal factors from contacting intestinal epithelial cells (IECs). IgA is induced by both T cell-dependent and -independent (TI) pathways. However, little is known about TI regulation. We report that IEC endoplasmic reticulum (ER) stress induces a polyreactive IgA response, which is protective against enteric inflammation. IEC ER stress causes TI and microbiota-independent expansion and activation of peritoneal B1b cells, which culminates in increased lamina propria and luminal IgA. Increased numbers of IgA-producing plasma cells were observed in healthy humans with defective autophagy, who are known to exhibit IEC ER stress. Upon ER stress, IECs communicate signals to the peritoneum that induce a barrier-protective TI IgA response.

Original language	English
Pages (from-to)	993-998
Number of pages	6
Journal	Science
Volume	363
Issue number	6430
DOIs	https://doi.org/10.1126/science.aat7186
Publication status	Published - 1 Mar 2019
Externally published	Yes

Keywords

Animals
Autophagy
Autophagy-Related Proteins/genetics
Endoplasmic Reticulum Stress
Epithelial Cells/immunology
Humans
Immunity, Mucosal
Immunoglobulin A/immunology
Inflammation
Intestinal Mucosa/immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Plasma Cells/immunology
Tissue Culture Techniques
X-Box Binding Protein 1/genetics

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10.1126/science.aat7186

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Grootjans, J., Krupka, N., Hosomi, S., Matute, J. D., Hanley, T., Saveljeva, S., Gensollen, T., Heijmans, J., Li, H., Limenitakis, J. P., Ganal-Vonarburg, S. C., Suo, S., Luoma, A. M., Shimodaira, Y., Duan, J., Shih, D. Q., Conner, M. E., Glickman, J. N., Fuhler, G. M., ... Blumberg, R. S. (2019). Epithelial endoplasmic reticulum stress orchestrates a protective IgA response. Science, 363(6430), 993-998. https://doi.org/10.1126/science.aat7186

@article{d93250b74a4648e69ae622ba0c945d8b,

title = "Epithelial endoplasmic reticulum stress orchestrates a protective IgA response",

abstract = "Immunoglobulin A (IgA) is the major secretory immunoglobulin isotype found at mucosal surfaces, where it regulates microbial commensalism and excludes luminal factors from contacting intestinal epithelial cells (IECs). IgA is induced by both T cell-dependent and -independent (TI) pathways. However, little is known about TI regulation. We report that IEC endoplasmic reticulum (ER) stress induces a polyreactive IgA response, which is protective against enteric inflammation. IEC ER stress causes TI and microbiota-independent expansion and activation of peritoneal B1b cells, which culminates in increased lamina propria and luminal IgA. Increased numbers of IgA-producing plasma cells were observed in healthy humans with defective autophagy, who are known to exhibit IEC ER stress. Upon ER stress, IECs communicate signals to the peritoneum that induce a barrier-protective TI IgA response.",

keywords = "Animals, Autophagy, Autophagy-Related Proteins/genetics, Endoplasmic Reticulum Stress, Epithelial Cells/immunology, Humans, Immunity, Mucosal, Immunoglobulin A/immunology, Inflammation, Intestinal Mucosa/immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Plasma Cells/immunology, Tissue Culture Techniques, X-Box Binding Protein 1/genetics",

author = "Joep Grootjans and Niklas Krupka and Shuhei Hosomi and Matute, \{Juan D\} and Thomas Hanley and Svetlana Saveljeva and Thomas Gensollen and Jarom Heijmans and Hai Li and Limenitakis, \{Julien P\} and Ganal-Vonarburg, \{Stephanie C\} and Shengbao Suo and Luoma, \{Adrienne M\} and Yosuke Shimodaira and Jinzhi Duan and Shih, \{David Q\} and Conner, \{Margaret E\} and Glickman, \{Jonathan N\} and Fuhler, \{Gwenny M\} and Palm, \{Noah W\} and \{de Zoete\}, \{Marcel R\} and \{van der Woude\}, \{C Janneke\} and Guo-Cheng Yuan and Wucherpfennig, \{Kai W\} and Targan, \{Stephan R\} and Philip Rosenstiel and Flavell, \{Richard A\} and McCoy, \{Kathy D\} and Macpherson, \{Andrew J\} and Arthur Kaser and Blumberg, \{Richard S\}",

note = "Funding Information: This work was supported by NIH grants DK044319, DK051362, DK053056, and DK088199; the Harvard Digestive Diseases Center (HDDC) DK034854 (R.S.B.); the Wellcome Trust Senior Investigator Award 106260/Z/14/Z, Evelyn Trust 13/27 (A.K.); the HORIZON2020/European Research Council Consolidator Grant 648889 (A.K.); the National Institute for Health Research Cambridge BRC Cell Phenotyping Hub (A.K.); Rubicon grant 825.13.012, Netherlands Organization for Scientific Research (J.G.); JSPS KAKENHI grant number 2689323 and 16K19162, Japan Foundation for Applied Enzymology (S.H.); NIH and NIAID grants R01AI24998 and R21AI117220 (M.E.C); Deutsche Forschungsgemeinschaft grant KR 4749/1-1 (N.K.); NIH NCI grant R01 CA238039 (K.W.W.); DFG ExC Precision Medicine in Chronic Inflammation, H2020 SYSCID \#733100 and DFG CRC1182, C2 (P.R.); and Pediatric Scientist Development Program K12-HD000850 (J.D.M.). The Howard Hughes Medical Institute supports R.A.F. Publisher Copyright: {\textcopyright} 2019 The Authors, some rights reserved. All rights reserved. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2019",

month = mar,

day = "1",

doi = "10.1126/science.aat7186",

language = "English",

volume = "363",

pages = "993--998",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6430",

}

Grootjans, J, Krupka, N, Hosomi, S, Matute, JD, Hanley, T, Saveljeva, S, Gensollen, T, Heijmans, J, Li, H, Limenitakis, JP, Ganal-Vonarburg, SC, Suo, S, Luoma, AM, Shimodaira, Y, Duan, J, Shih, DQ, Conner, ME, Glickman, JN, Fuhler, GM, Palm, NW, de Zoete, MR, van der Woude, CJ, Yuan, G-C, Wucherpfennig, KW, Targan, SR, Rosenstiel, P, Flavell, RA, McCoy, KD, Macpherson, AJ, Kaser, A & Blumberg, RS 2019, 'Epithelial endoplasmic reticulum stress orchestrates a protective IgA response', Science, vol. 363, no. 6430, pp. 993-998. https://doi.org/10.1126/science.aat7186

TY - JOUR

T1 - Epithelial endoplasmic reticulum stress orchestrates a protective IgA response

AU - Grootjans, Joep

AU - Krupka, Niklas

AU - Hosomi, Shuhei

AU - Matute, Juan D

AU - Hanley, Thomas

AU - Saveljeva, Svetlana

AU - Gensollen, Thomas

AU - Heijmans, Jarom

AU - Li, Hai

AU - Limenitakis, Julien P

AU - Ganal-Vonarburg, Stephanie C

AU - Suo, Shengbao

AU - Luoma, Adrienne M

AU - Shimodaira, Yosuke

AU - Duan, Jinzhi

AU - Shih, David Q

AU - Conner, Margaret E

AU - Glickman, Jonathan N

AU - Fuhler, Gwenny M

AU - Palm, Noah W

AU - de Zoete, Marcel R

AU - van der Woude, C Janneke

AU - Yuan, Guo-Cheng

AU - Wucherpfennig, Kai W

AU - Targan, Stephan R

AU - Rosenstiel, Philip

AU - Flavell, Richard A

AU - McCoy, Kathy D

AU - Macpherson, Andrew J

AU - Kaser, Arthur

AU - Blumberg, Richard S

N1 - Funding Information: This work was supported by NIH grants DK044319, DK051362, DK053056, and DK088199; the Harvard Digestive Diseases Center (HDDC) DK034854 (R.S.B.); the Wellcome Trust Senior Investigator Award 106260/Z/14/Z, Evelyn Trust 13/27 (A.K.); the HORIZON2020/European Research Council Consolidator Grant 648889 (A.K.); the National Institute for Health Research Cambridge BRC Cell Phenotyping Hub (A.K.); Rubicon grant 825.13.012, Netherlands Organization for Scientific Research (J.G.); JSPS KAKENHI grant number 2689323 and 16K19162, Japan Foundation for Applied Enzymology (S.H.); NIH and NIAID grants R01AI24998 and R21AI117220 (M.E.C); Deutsche Forschungsgemeinschaft grant KR 4749/1-1 (N.K.); NIH NCI grant R01 CA238039 (K.W.W.); DFG ExC Precision Medicine in Chronic Inflammation, H2020 SYSCID #733100 and DFG CRC1182, C2 (P.R.); and Pediatric Scientist Development Program K12-HD000850 (J.D.M.). The Howard Hughes Medical Institute supports R.A.F. Publisher Copyright: © 2019 The Authors, some rights reserved. All rights reserved. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Immunoglobulin A (IgA) is the major secretory immunoglobulin isotype found at mucosal surfaces, where it regulates microbial commensalism and excludes luminal factors from contacting intestinal epithelial cells (IECs). IgA is induced by both T cell-dependent and -independent (TI) pathways. However, little is known about TI regulation. We report that IEC endoplasmic reticulum (ER) stress induces a polyreactive IgA response, which is protective against enteric inflammation. IEC ER stress causes TI and microbiota-independent expansion and activation of peritoneal B1b cells, which culminates in increased lamina propria and luminal IgA. Increased numbers of IgA-producing plasma cells were observed in healthy humans with defective autophagy, who are known to exhibit IEC ER stress. Upon ER stress, IECs communicate signals to the peritoneum that induce a barrier-protective TI IgA response.

AB - Immunoglobulin A (IgA) is the major secretory immunoglobulin isotype found at mucosal surfaces, where it regulates microbial commensalism and excludes luminal factors from contacting intestinal epithelial cells (IECs). IgA is induced by both T cell-dependent and -independent (TI) pathways. However, little is known about TI regulation. We report that IEC endoplasmic reticulum (ER) stress induces a polyreactive IgA response, which is protective against enteric inflammation. IEC ER stress causes TI and microbiota-independent expansion and activation of peritoneal B1b cells, which culminates in increased lamina propria and luminal IgA. Increased numbers of IgA-producing plasma cells were observed in healthy humans with defective autophagy, who are known to exhibit IEC ER stress. Upon ER stress, IECs communicate signals to the peritoneum that induce a barrier-protective TI IgA response.

KW - Animals

KW - Autophagy

KW - Autophagy-Related Proteins/genetics

KW - Endoplasmic Reticulum Stress

KW - Epithelial Cells/immunology

KW - Humans

KW - Immunity, Mucosal

KW - Immunoglobulin A/immunology

KW - Inflammation

KW - Intestinal Mucosa/immunology

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Plasma Cells/immunology

KW - Tissue Culture Techniques

KW - X-Box Binding Protein 1/genetics

UR - https://www.scopus.com/pages/publications/85062394869

U2 - 10.1126/science.aat7186

DO - 10.1126/science.aat7186

M3 - Article

C2 - 30819965

SN - 0036-8075

VL - 363

SP - 993

EP - 998

JO - Science

JF - Science

IS - 6430

ER -

Epithelial endoplasmic reticulum stress orchestrates a protective IgA response

Abstract

Keywords

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