Tetraspanin CD37 regulates β2 integrin-mediated adhesion and migration in neutrophils

Janet L. Wee, Keith E. Schulze, Eleanor L. Jones, Louisa Yeung, Qiang Cheng, Candida F. Pereira, Adam Costin, Georg Ramm, Annemiek B. Van Spriel, Michael J. Hickey, Mark D. Wright

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Deciphering the molecular basis of leukocyte recruitment is critical to the understanding of inflammation. In this study, we investigated the contribution of the tetraspanin CD37 to this key process. CD37-deficient mice showed impaired neutrophil recruitment in a peritonitis model. Intravital microscopic analysis indicated that the absence of CD37 impaired the capacity of leukocytes to follow a CXCL1 chemotactic gradient accurately in the interstitium. Moreover, analysis of CXCL1-induced leukocyte-endothelial cell interactions in postcapillary venules revealed that CXCL1-induced neutrophil adhesion and transmigration were reduced in the absence of CD37, consistent with a reduced capacity to undergo β2 integrin-dependent adhesion. This result was supported by in vitro flow chamber experiments that demonstrated an impairment in adhesion of CD37-deficient neutrophils to the β2 integrin ligand, ICAM-1, despite the normal display of high-affinity β2 integrins. Superresolution microscopic assessment of localization of CD37 and CD18 in ICAM-1-adherent neutrophils demonstrated that these molecules do not significantly cocluster in the cell membrane, arguing against the possibility that CD37 regulates β2 integrin function via a direct molecular interaction. Moreover, CD37 ablation did not affect β2 integrin clustering. In contrast, the absence of CD37 in neutrophils impaired actin polymerization, cell spreading and polarization, dysregulated Rac-1 activation, and accelerated β2 integrin internalization. Together, these data indicate that CD37 promotes neutrophil adhesion and recruitment via the promotion of cytoskeletal function downstream of integrin-mediated adhesion.

Original languageEnglish
Pages (from-to)5770-5779
Number of pages10
JournalJournal of Immunology
Volume195
Issue number12
DOIs
Publication statusPublished - 15 Dec 2015

Cite this

Wee, J. L., Schulze, K. E., Jones, E. L., Yeung, L., Cheng, Q., Pereira, C. F., ... Wright, M. D. (2015). Tetraspanin CD37 regulates β2 integrin-mediated adhesion and migration in neutrophils. Journal of Immunology, 195(12), 5770-5779. https://doi.org/10.4049/jimmunol.1402414
Wee, Janet L. ; Schulze, Keith E. ; Jones, Eleanor L. ; Yeung, Louisa ; Cheng, Qiang ; Pereira, Candida F. ; Costin, Adam ; Ramm, Georg ; Van Spriel, Annemiek B. ; Hickey, Michael J. ; Wright, Mark D. / Tetraspanin CD37 regulates β2 integrin-mediated adhesion and migration in neutrophils. In: Journal of Immunology. 2015 ; Vol. 195, No. 12. pp. 5770-5779.
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abstract = "Deciphering the molecular basis of leukocyte recruitment is critical to the understanding of inflammation. In this study, we investigated the contribution of the tetraspanin CD37 to this key process. CD37-deficient mice showed impaired neutrophil recruitment in a peritonitis model. Intravital microscopic analysis indicated that the absence of CD37 impaired the capacity of leukocytes to follow a CXCL1 chemotactic gradient accurately in the interstitium. Moreover, analysis of CXCL1-induced leukocyte-endothelial cell interactions in postcapillary venules revealed that CXCL1-induced neutrophil adhesion and transmigration were reduced in the absence of CD37, consistent with a reduced capacity to undergo β2 integrin-dependent adhesion. This result was supported by in vitro flow chamber experiments that demonstrated an impairment in adhesion of CD37-deficient neutrophils to the β2 integrin ligand, ICAM-1, despite the normal display of high-affinity β2 integrins. Superresolution microscopic assessment of localization of CD37 and CD18 in ICAM-1-adherent neutrophils demonstrated that these molecules do not significantly cocluster in the cell membrane, arguing against the possibility that CD37 regulates β2 integrin function via a direct molecular interaction. Moreover, CD37 ablation did not affect β2 integrin clustering. In contrast, the absence of CD37 in neutrophils impaired actin polymerization, cell spreading and polarization, dysregulated Rac-1 activation, and accelerated β2 integrin internalization. Together, these data indicate that CD37 promotes neutrophil adhesion and recruitment via the promotion of cytoskeletal function downstream of integrin-mediated adhesion.",
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Wee, JL, Schulze, KE, Jones, EL, Yeung, L, Cheng, Q, Pereira, CF, Costin, A, Ramm, G, Van Spriel, AB, Hickey, MJ & Wright, MD 2015, 'Tetraspanin CD37 regulates β2 integrin-mediated adhesion and migration in neutrophils' Journal of Immunology, vol. 195, no. 12, pp. 5770-5779. https://doi.org/10.4049/jimmunol.1402414

Tetraspanin CD37 regulates β2 integrin-mediated adhesion and migration in neutrophils. / Wee, Janet L.; Schulze, Keith E.; Jones, Eleanor L.; Yeung, Louisa; Cheng, Qiang; Pereira, Candida F.; Costin, Adam; Ramm, Georg; Van Spriel, Annemiek B.; Hickey, Michael J.; Wright, Mark D.

In: Journal of Immunology, Vol. 195, No. 12, 15.12.2015, p. 5770-5779.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Wee, Janet L.

AU - Schulze, Keith E.

AU - Jones, Eleanor L.

AU - Yeung, Louisa

AU - Cheng, Qiang

AU - Pereira, Candida F.

AU - Costin, Adam

AU - Ramm, Georg

AU - Van Spriel, Annemiek B.

AU - Hickey, Michael J.

AU - Wright, Mark D.

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AB - Deciphering the molecular basis of leukocyte recruitment is critical to the understanding of inflammation. In this study, we investigated the contribution of the tetraspanin CD37 to this key process. CD37-deficient mice showed impaired neutrophil recruitment in a peritonitis model. Intravital microscopic analysis indicated that the absence of CD37 impaired the capacity of leukocytes to follow a CXCL1 chemotactic gradient accurately in the interstitium. Moreover, analysis of CXCL1-induced leukocyte-endothelial cell interactions in postcapillary venules revealed that CXCL1-induced neutrophil adhesion and transmigration were reduced in the absence of CD37, consistent with a reduced capacity to undergo β2 integrin-dependent adhesion. This result was supported by in vitro flow chamber experiments that demonstrated an impairment in adhesion of CD37-deficient neutrophils to the β2 integrin ligand, ICAM-1, despite the normal display of high-affinity β2 integrins. Superresolution microscopic assessment of localization of CD37 and CD18 in ICAM-1-adherent neutrophils demonstrated that these molecules do not significantly cocluster in the cell membrane, arguing against the possibility that CD37 regulates β2 integrin function via a direct molecular interaction. Moreover, CD37 ablation did not affect β2 integrin clustering. In contrast, the absence of CD37 in neutrophils impaired actin polymerization, cell spreading and polarization, dysregulated Rac-1 activation, and accelerated β2 integrin internalization. Together, these data indicate that CD37 promotes neutrophil adhesion and recruitment via the promotion of cytoskeletal function downstream of integrin-mediated adhesion.

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Wee JL, Schulze KE, Jones EL, Yeung L, Cheng Q, Pereira CF et al. Tetraspanin CD37 regulates β2 integrin-mediated adhesion and migration in neutrophils. Journal of Immunology. 2015 Dec 15;195(12):5770-5779. https://doi.org/10.4049/jimmunol.1402414