Intercrypt sentinel macrophages tune antibacterial NF-κB responses in gut epithelial cells via TNF

Intestinal epithelial cell (IEC) NF-κB signaling regulates the balance between mucosal homeostasis and inflammation. It is not fully understood which signals tune this balance and how bacterial exposure elicits the process. Pure LPS induces epithelial NF-κB activation in vivo. However, we found that...

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Published in:	The Journal of experimental medicine Vol. 218; no. 11
Main Authors:	Hausmann, Annika, Felmy, Boas, Kunz, Leo, Kroon, Sanne, Berthold, Dorothée Lisa, Ganz, Giverny, Sandu, Ioana, Nakamura, Toshihiro, Zangger, Nathan Sébastien, Zhang, Yang, Dolowschiak, Tamas, Fattinger, Stefan Alexander, Furter, Markus, Müller-Hauser, Anna Angelika, Barthel, Manja, Vlantis, Katerina, Wachsmuth, Laurens, Kisielow, Jan, Tortola, Luigi, Heide, Danijela, Heikenwälder, Mathias, Oxenius, Annette, Kopf, Manfred, Schroeder, Timm, Pasparakis, Manolis, Sellin, Mikael Erik, Hardt, Wolf-Dietrich
Format:	Journal Article
Language:	English
Published:	United States Rockefeller University Press 01-11-2021
Subjects:	Animals Anti-Bacterial Agents - metabolism Epithelial Cells - metabolism Gene Expression Regulation - physiology Infectious Disease and Host Defense Inflammation - metabolism Innate Immunity and Inflammation Intestinal Mucosa - metabolism Intestines - metabolism Macrophages - drug effects Mice Mice, Inbred C57BL Mucosal Immunology NF-kappa B - metabolism Signal Transduction - physiology Tumor Necrosis Factors - metabolism
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Summary:	Intestinal epithelial cell (IEC) NF-κB signaling regulates the balance between mucosal homeostasis and inflammation. It is not fully understood which signals tune this balance and how bacterial exposure elicits the process. Pure LPS induces epithelial NF-κB activation in vivo. However, we found that in mice, IECs do not respond directly to LPS. Instead, tissue-resident lamina propria intercrypt macrophages sense LPS via TLR4 and rapidly secrete TNF to elicit epithelial NF-κB signaling in their immediate neighborhood. This response pattern is relevant also during oral enteropathogen infection. The macrophage-TNF-IEC axis avoids responses to luminal microbiota LPS but enables crypt- or tissue-scale epithelial NF-κB responses in proportion to the microbial threat. Thereby, intercrypt macrophages fulfill important sentinel functions as first responders to Gram-negative microbes breaching the epithelial barrier. The tunability of this crypt response allows the induction of defense mechanisms at an appropriate scale according to the localization and intensity of microbial triggers.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 A. Hausmann and B. Felmy contributed equally to this paper. Disclosures: The authors declare no competing interests exist.
ISSN:	0022-1007 1540-9538 1540-9538
DOI:	10.1084/jem.20210862