Glial cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence

Bibliographic Details
Main Author: García Cassani, Bethania
Publication Date: 2016
Language: eng
Source: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
Download full: http://hdl.handle.net/10451/28400
Summary: Tese de doutoramento, Ciências Biomédicas (Imunologia), Universidade de Lisboa, Faculdade de Medicina, 2017
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spelling Glial cell-derived neuroregulators control type 3 innate lymphoid cells and gut defenceNeurogliaNeurotransmissoresLinfócitosIntestinosImunologiaTeses de doutoramento - 2017Domínio/Área Científica::Ciências Médicas::Medicina BásicaTese de doutoramento, Ciências Biomédicas (Imunologia), Universidade de Lisboa, Faculdade de Medicina, 2017In this thesis we demonstrate that three distinct players form a novel multi-tissue defence unit in the intestinal wall: group 3 of innate lymphoid cells (ILC3s), intestinal epithelial cells and enteric glial cells (EGCs). This interplay reveals a neuro-immune interaction unit that regulates epithelial homeostasis and mucosal defense. ILC3s are major regulators at mucosal surfaces being critical in tissue repair and in the maintenance of gut homeostasis. Intestinal ILC3 – that mainly aggregate into cryptopatches - integrate environmental signals leading to the production of the proinflammatory cytokines IL-22 and IL-17. IL-22 in turn induces intestinal epithelial cells to produce antimicrobial peptides and mucus. We found that ILC3s express high levels of RET, a neuroregulatory receptor for GDNF family ligands (GFLs). In order to address the effect of RET in ILC3s development and function RET-deficient mice foetal liver chimeras were analyzed. Interestingly a decrease of IL-22 expressing ILC3s was observed when compared to WT controls. In addition a RET gain of function model (RetMEN2B) resulted in increased IL-22 expressing ILC3s. In line with these experiments, cell-autonomous ablation of RET in Rorγt expressing cells was performed. RorγtCreRetfl/fl, (RetΔ) mice had decrease IL-22 expressing ILC3s and a reduction of epithelial reactivity genes such as mucins and defensins comparing with their littermate controls. Upon infection with the attaching and effacing bacteria Citrobacter rodentium, RetΔ mice had marked gut inflammation, reduced IL-22 producing ILC3, increased C. rodentium infection and translocation, reduced epithelial reactivity genes, increased weight loss and reduced survival. All these data together, suggest that RET cell autonomous ILC3 signals regulate IL-22 production. Signals downstream of Ret were regulated via GFLs which directly controled rapid phosphorylation of the p38 MAPK/ERK-AKT cascade and STAT3 activation in ILC3s. In turn, STAT3 bound to the Il22 promoter to induce transcription. Finally, we found that enteric glial cells integrated commensal and environmental signals to produce GFLs that control IL-22 production. Physical localization of glial cells in the vicinity of ILC3 was observed taking advantage of double reporter mice for GFAP (glial fibrillary acidic protein) and RET. Enteric glial cells had a stellate shape morphology, projecting into cryptopatches. In vitro co-culture studies showed EGCs capacity to produce GFLs in response to TLR2 and TLR4 activation and IL-1β and IL-33 stimulation, promoting IL-22 production by ILC3s. In vivo studies with DSS induced colitis in glial specific Myd88 deficient mice (Gfap-Cre.Myd88Δ) showed an increase of gut inflammation and weight loss along with a reduced expression of intestinal GFLs and ILC3-derived IL-22 levels compared with their littermate controls. When infected with Citrobacter Rodentium Myd88 deficient mice exhibited a pronounced susceptibility to bowel inflammation and infection. In summary, we were able to show that the enteric glial cells sense environmental cues through MYD88 to produce GFLs that in turn activate RET expressing ILC3s and via MAP kinase and STAT3 induce the transcription of Il22. The production of IL-22 promotes the expression of defence and repair genes. Thus, this novel glial-ILC3 epithelial unit is critical in the maintenance of intestinal homeostasis providing protection and repairing the epithelial barrier after injury.Fernandes, Henrique Veiga, 1972-Repositório da Universidade de LisboaGarcía Cassani, Bethania2017-07-18T16:48:27Z201720162017-01-01T00:00:00Zdoctoral thesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10451/28400TID:101518676enginfo:eu-repo/semantics/openAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2025-03-17T13:41:38Zoai:repositorio.ulisboa.pt:10451/28400Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-29T02:51:19.041730Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse
dc.title.none.fl_str_mv Glial cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence
title Glial cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence
spellingShingle Glial cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence
García Cassani, Bethania
Neuroglia
Neurotransmissores
Linfócitos
Intestinos
Imunologia
Teses de doutoramento - 2017
Domínio/Área Científica::Ciências Médicas::Medicina Básica
title_short Glial cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence
title_full Glial cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence
title_fullStr Glial cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence
title_full_unstemmed Glial cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence
title_sort Glial cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence
author García Cassani, Bethania
author_facet García Cassani, Bethania
author_role author
dc.contributor.none.fl_str_mv Fernandes, Henrique Veiga, 1972-
Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv García Cassani, Bethania
dc.subject.por.fl_str_mv Neuroglia
Neurotransmissores
Linfócitos
Intestinos
Imunologia
Teses de doutoramento - 2017
Domínio/Área Científica::Ciências Médicas::Medicina Básica
topic Neuroglia
Neurotransmissores
Linfócitos
Intestinos
Imunologia
Teses de doutoramento - 2017
Domínio/Área Científica::Ciências Médicas::Medicina Básica
description Tese de doutoramento, Ciências Biomédicas (Imunologia), Universidade de Lisboa, Faculdade de Medicina, 2017
publishDate 2016
dc.date.none.fl_str_mv 2016
2017-07-18T16:48:27Z
2017
2017-01-01T00:00:00Z
dc.type.driver.fl_str_mv doctoral thesis
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/28400
TID:101518676
url http://hdl.handle.net/10451/28400
identifier_str_mv TID:101518676
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron:RCAAP
instname_str FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron_str RCAAP
institution RCAAP
reponame_str Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
collection Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
repository.name.fl_str_mv Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
repository.mail.fl_str_mv info@rcaap.pt
_version_ 1833601507600105472

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