A non-canonical type 2 immune response coordinates tuberculous granuloma formation and epithelialization.
Animals
Animals, Genetically Modified
/ genetics
Cadherins
/ genetics
Cell Differentiation
Disease Models, Animal
Epithelioid Cells
/ cytology
Granuloma
/ immunology
Hematopoietic Stem Cells
/ cytology
Immunity
/ physiology
Interferon-gamma
/ metabolism
Interleukin-12
/ metabolism
Macrophages
/ cytology
Mycobacterium Infections, Nontuberculous
/ immunology
Mycobacterium marinum
/ isolation & purification
Necrosis
RNA, Guide, Kinetoplastida
/ metabolism
Receptors, Interleukin-4
/ antagonists & inhibitors
STAT6 Transcription Factor
/ antagonists & inhibitors
Signal Transduction
Zebrafish
/ growth & development
IL4R
Mycobacterium
STAT6
epithelialization
granuloma
macrophage
tuberculosis
zebrafish
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
01 04 2021
01 04 2021
Historique:
received:
10
03
2020
revised:
03
11
2020
accepted:
22
02
2021
pubmed:
25
3
2021
medline:
21
10
2021
entrez:
24
3
2021
Statut:
ppublish
Résumé
The central pathogen-immune interface in tuberculosis is the granuloma, a complex host immune structure that dictates infection trajectory and physiology. Granuloma macrophages undergo a dramatic transition in which entire epithelial modules are induced and define granuloma architecture. In tuberculosis, relatively little is known about the host signals that trigger this transition. Using the zebrafish-Mycobacterium marinum model, we identify the basis of granuloma macrophage transformation. Single-cell RNA-sequencing analysis of zebrafish granulomas and analysis of Mycobacterium tuberculosis-infected macaques reveal that, even in the presence of robust type 1 immune responses, countervailing type 2 signals associate with macrophage epithelialization. We find that type 2 immune signaling, mediated via stat6, is absolutely required for epithelialization and granuloma formation. In mixed chimeras, stat6 acts cell autonomously within macrophages, where it is required for epithelioid transformation and incorporation into necrotic granulomas. These findings establish the signaling pathway that produces the hallmark structure of mycobacterial infection.
Identifiants
pubmed: 33761328
pii: S0092-8674(21)00235-X
doi: 10.1016/j.cell.2021.02.046
pmc: PMC8055144
mid: NIHMS1677912
pii:
doi:
Substances chimiques
Cadherins
0
RNA, Guide
0
Receptors, Interleukin-4
0
STAT6 Transcription Factor
0
Interleukin-12
187348-17-0
Interferon-gamma
82115-62-6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1757-1774.e14Subventions
Organisme : NIAID NIH HHS
ID : R01 AI127715
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI130236
Pays : United States
Organisme : NIH HHS
ID : P51 OD011133
Pays : United States
Organisme : NIAID NIH HHS
ID : R43 AI134249
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI125517
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI111943
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM136627
Pays : United States
Organisme : NIH HHS
ID : P51 OD011104
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014236
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG051428
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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