The Rac-GEF Tiam1 controls integrin-dependent neutrophil responses

Front Immunol. 2023 Nov 21:14:1223653. doi: 10.3389/fimmu.2023.1223653. eCollection 2023.

Abstract

Rac GTPases are required for neutrophil adhesion and migration, and for the neutrophil effector responses that kill pathogens. These Rac-dependent functions are impaired when neutrophils lack the activators of Rac, Rac-GEFs from the Prex, Vav, and Dock families. In this study, we demonstrate that Tiam1 is also expressed in neutrophils, governing focal complexes, actin cytoskeletal dynamics, polarisation, and migration, in a manner depending on the integrin ligand to which the cells adhere. Tiam1 is dispensable for the generation of reactive oxygen species but mediates degranulation and NETs release in adherent neutrophils, as well as the killing of bacteria. In vivo, Tiam1 is required for neutrophil recruitment during aseptic peritonitis and for the clearance of Streptococcus pneumoniae during pulmonary infection. However, Tiam1 functions differently to other Rac-GEFs. Instead of promoting neutrophil adhesion to ICAM1 and stimulating β2 integrin activity as could be expected, Tiam1 restricts these processes. In accordance with these paradoxical inhibitory roles, Tiam1 limits the fMLP-stimulated activation of Rac1 and Rac2 in adherent neutrophils, rather than activating Rac as expected. Tiam1 promotes the expression of several regulators of small GTPases and cytoskeletal dynamics, including αPix, Psd4, Rasa3, and Tiam2. It also controls the association of Rasa3, and potentially αPix, Git2, Psd4, and 14-3-3ζ/δ, with Rac. We propose these latter roles of Tiam1 underlie its effects on Rac and β2 integrin activity and on cell responses. Hence, Tiam1 is a novel regulator of Rac-dependent neutrophil responses that functions differently to other known neutrophil Rac-GEFs.

Keywords: Dock2; Prex1; Rac; Rac-GEF; Tiam1; Vav; neutrophils; small GTPase.

MeSH terms

  • 14-3-3 Proteins / metabolism
  • CD18 Antigens / metabolism
  • Humans
  • Integrins* / metabolism
  • Neutrophils* / metabolism
  • rac GTP-Binding Proteins / metabolism

Substances

  • Integrins
  • rac GTP-Binding Proteins
  • 14-3-3 Proteins
  • CD18 Antigens

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. MB, PM and CP received PhD studentships from the UK Biotechnology and Biological Sciences Research Council (BBSRC) Doctoral Training Programme. SC is the recipient of a targeted PhD studentship from the UK Medical Research Council (MRC). A-KJ was funded by project grant BB/I02154X/1 from the BBSRC. The project was funded by Institute Strategic Programme Grant BB/P013384/1 from the BBSRC to the Babraham Institute Signalling Programme.