@article{c6032c0677c7465ca5558dd04f08ab49,
title = "Enteric pathogens induce tissue tolerance and prevent neuronal loss from subsequent infections",
abstract = "The enteric nervous system (ENS) controls several intestinal functions including motility and nutrient handling, which can be disrupted by infection-induced neuropathies or neuronal cell death. We investigated possible tolerance mechanisms preventing neuronal loss and disruption in gut motility after pathogen exposure. We found that following enteric infections, muscularis macrophages (MMs) acquire a tissue-protective phenotype that prevents neuronal loss, dysmotility, and maintains energy balance during subsequent challenge with unrelated pathogens. Bacteria-induced neuroprotection relied on activation of gut-projecting sympathetic neurons and signaling via β2-adrenergic receptors (β2AR) on MMs. In contrast, helminth-mediated neuroprotection was dependent on T cells and systemic production of interleukin (IL)-4 and IL-13 by eosinophils, which induced arginase-expressing MMs that prevented neuronal loss from an unrelated infection located in a different intestinal region. Collectively, these data suggest that distinct enteric pathogens trigger a state of disease or tissue tolerance that preserves ENS number and functionality.",
keywords = "enteric infections, enteric neurons, eosinophils, macrophages, neuroimmunology, small intestine",
author = "Tomasz Ahrends and Beg{\"u}m Aydin and Fanny Matheis and Classon, {Cajsa H.} and Fran{\c c}ois Marchildon and Furtado, {Gl{\'a}ucia C.} and Lira, {S{\'e}rgio A.} and Daniel Mucida",
note = "Funding Information: We thank all Mucida Lab members and Rockefeller University employees for their continuous assistance, A. Rogoz and S. Gonzalez for the maintenance of mice, RU Bio-imaging Research Center for assistance with image acquisition analysis, and Tiago B.R. Castro for assembling the RNA-seq analysis platform for the lab. We thank E. Jacobsen for providing iPHIL and Epxtm1.1(cre)Jlee mouse strains, M. Merad for the anti-CSF1R hybridoma, V. Lenon for anti-Anna-1 antibody, S. Galli and K. Matsushita for the Sv larvae, I. Brodsky for Yp, J. Lafaille for H. polygyrus larvae, Jun-ichi Miyazaki for pCAGGS-IL5 plasmid, J. von Moltke for suggestions in the succinate experiments, and P. Cohen for CLAMS cage experiments. We also thank the Victora and Lafaille labs for fruitful discussions. This work was supported by NIH Transformative (R01DK116646 and R01DK126407), Kenneth Rainin Foundation, andFood Allergy FARE/FASI Consortium to D.M. T.A. is a Human Frontier of Science Program postdoctoral fellow. B.A. is a Simons Foundation junior fellow. D.M. is an investigator of the Howard Hughes Medical Institute. T.A. initiated, designed, and performed the research and wrote the manuscript. B.A. F. Marchildon (CLAMS cages), F. Matheis and C.H.C. designed and performed experiments. G.C.F. and S.A.L. generated the cpa3DTR-tdTomato mice. D.M. conceived, initiated, designed, and supervised the research and wrote the manuscript. All authors revised and edited the manuscript and figures. The authors declare no competing interests. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Funding Information: We thank all Mucida Lab members and Rockefeller University employees for their continuous assistance, A. Rogoz and S. Gonzalez for the maintenance of mice, RU Bio-imaging Research Center for assistance with image acquisition analysis, and Tiago B.R. Castro for assembling the RNA-seq analysis platform for the lab. We thank E. Jacobsen for providing iPHIL and Epx tm1.1(cre)Jlee mouse strains, M. Merad for the anti-CSF1R hybridoma, V. Lenon for anti-Anna-1 antibody, S. Galli and K. Matsushita for the Sv larvae, I. Brodsky for Yp, J. Lafaille for H. polygyrus larvae, Jun-ichi Miyazaki for pCAGGS-IL5 plasmid, J. von Moltke for suggestions in the succinate experiments, and P. Cohen for CLAMS cage experiments. We also thank the Victora and Lafaille labs for fruitful discussions. This work was supported by NIH Transformative ( R01DK116646 and R01DK126407 ), Kenneth Rainin Foundation, and Food Allergy FARE/FASI Consortium to D.M.. T.A. is a Human Frontier of Science Program postdoctoral fellow. B.A. is a Simons Foundation junior fellow. D.M. is an investigator of the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = nov,
day = "11",
doi = "10.1016/j.cell.2021.10.004",
language = "English",
volume = "184",
pages = "5715--5727.e12",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "23",
}