ZFIN ID: ZDB-PUB-210325-13
A non-canonical type 2 immune response coordinates tuberculous granuloma formation and epithelialization
Cronan, M.R., Hughes, E.J., Brewer, W.J., Viswanathan, G., Hunt, E.G., Singh, B., Mehra, S., Oehlers, S.H., Gregory, S.G., Kaushal, D., Tobin, D.M.
Date: 2021
Source: Cell   184(7): 1757-1774.e14 (Journal)
Registered Authors: Cronan, Mark, Oehlers, Stefan, Tobin, David
Keywords: IL4R, Mycobacterium, STAT6, epithelialization, granuloma, macrophage, tuberculosis, zebrafish
Microarrays: GEO:GSE161712
MeSH Terms:
  • Animals
  • Animals, Genetically Modified/genetics
  • Animals, Genetically Modified/metabolism
  • Cadherins/genetics
  • Cadherins/metabolism
  • Cell Differentiation
  • Disease Models, Animal
  • Epithelioid Cells/cytology
  • Epithelioid Cells/immunology
  • Epithelioid Cells/metabolism
  • Granuloma/immunology
  • Granuloma/metabolism
  • Granuloma/pathology*
  • Hematopoietic Stem Cells/cytology
  • Hematopoietic Stem Cells/metabolism
  • Immunity/physiology*
  • Interferon-gamma/metabolism
  • Interleukin-12/metabolism
  • Macrophages/cytology
  • Macrophages/immunology
  • Macrophages/metabolism
  • Mycobacterium Infections, Nontuberculous/immunology
  • Mycobacterium Infections, Nontuberculous/pathology*
  • Mycobacterium marinum/isolation & purification
  • Mycobacterium marinum/physiology
  • Necrosis
  • RNA, Guide/metabolism
  • Receptors, Interleukin-4/antagonists & inhibitors
  • Receptors, Interleukin-4/genetics
  • Receptors, Interleukin-4/metabolism
  • STAT6 Transcription Factor/antagonists & inhibitors
  • STAT6 Transcription Factor/genetics
  • STAT6 Transcription Factor/metabolism
  • Signal Transduction
  • Zebrafish/growth & development
  • Zebrafish/metabolism
PubMed: 33761328 Full text @ Cell
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-Mycobacteriummarinum model, we identify the basis of granuloma macrophage transformation. Single-cell RNA-sequencing analysis of zebrafish granulomas and analysis of Mycobacteriumtuberculosis-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.