PAR-1 signaling on macrophages is required for effective in vivo delayed-type hypersensitivity responses

H. Wilkinson*, H. Leonard, D.X. Chen, T. Lawrence, M. Robson, P. Goossens, J.H. McVey, A. Dorling*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Web of Science)

Abstract

Delayed-type hypersensitivity (DTH) responses underpin chronic inflammation. Using a model of oxazolone-induced dermatitis and a combination of transgenic mice, adoptive cell transfer, and selective agonists/antagonists against protease activated receptors, we show that that PAR-1 signaling on macrophages by thrombin is required for effective granuloma formation. Using BM-derived macrophages (BMMs) in vitro, we show that thrombin signaling induced (a) downregulation of cell membrane reverse cholesterol transporter ABCA1 and (b) increased expression of IFN gamma receptor and enhanced co-localization within increased areas of cholesterol-rich membrane microdomains. These two key phenotypic changes combined to make thrombin-primed BMMs sensitive to M1 polarization by 1000-fold less IFN gamma, compared to resting BMMs. We confirm that changes in ABCA1 expression were directly responsible for the exquisite sensitivity to IFNg in vitro and for the impact on granuloma formation in vivo. These data indicate that PAR-1 signaling plays a hitherto unrecognized and critical role in DTH responses.
Original languageEnglish
Article number101981
Number of pages25
JournaliScience
Volume24
Issue number1
DOIs
Publication statusPublished - 22 Jan 2021

Keywords

  • cells
  • expression
  • inflammation
  • inhibition
  • lipid rafts
  • polarization
  • proinflammatory role
  • protease-activated receptors
  • thrombin
  • tissue factor
  • CELLS
  • PROINFLAMMATORY ROLE
  • THROMBIN
  • PROTEASE-ACTIVATED RECEPTORS
  • INHIBITION
  • INFLAMMATION
  • LIPID RAFTS
  • EXPRESSION
  • POLARIZATION
  • TISSUE FACTOR

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