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Integrin Cross-Talk Regulates the Human Neutrophil Response to Fungal β-Glucan in the Context of the Extracellular Matrix: A Prominent Role for VLA3 in the Antifungal Response

Courtney M. Johnson, Xian M. O’Brien, Angel S. Byrd, Valentina E. Parisi, Alex J. Loosely, Wei Li, Hadley Witt, Hafeez M. Faridi, Craig T. Lefort, Vineet Gupta, Minsoo Kim and Jonathan S. Reichner
J Immunol November 16, 2016, 1502381; DOI: https://doi.org/10.4049/jimmunol.1502381
Courtney M. Johnson
*Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Providence, RI 02903;
†Warren Alpert Medical School, Brown University, Providence, RI 02912;
‡Graduate Program in Pathobiology, Brown University, Providence, RI 02912;
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Xian M. O’Brien
*Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Providence, RI 02903;
†Warren Alpert Medical School, Brown University, Providence, RI 02912;
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Angel S. Byrd
*Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Providence, RI 02903;
†Warren Alpert Medical School, Brown University, Providence, RI 02912;
‡Graduate Program in Pathobiology, Brown University, Providence, RI 02912;
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Valentina E. Parisi
*Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Providence, RI 02903;
‡Graduate Program in Pathobiology, Brown University, Providence, RI 02912;
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Alex J. Loosely
§Department of Physics, Brown University, Providence, RI 02912;
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Wei Li
*Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Providence, RI 02903;
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Hadley Witt
*Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Providence, RI 02903;
†Warren Alpert Medical School, Brown University, Providence, RI 02912;
‡Graduate Program in Pathobiology, Brown University, Providence, RI 02912;
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Hafeez M. Faridi
¶Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612; and
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Craig T. Lefort
*Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Providence, RI 02903;
†Warren Alpert Medical School, Brown University, Providence, RI 02912;
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Vineet Gupta
¶Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612; and
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Minsoo Kim
‖David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642
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Jonathan S. Reichner
*Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Providence, RI 02903;
†Warren Alpert Medical School, Brown University, Providence, RI 02912;
‡Graduate Program in Pathobiology, Brown University, Providence, RI 02912;
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Abstract

Candida albicans infection produces elongated hyphae resistant to phagocytic clearance compelling alternative neutrophil effector mechanisms to destroy these physically large microbial structures. Additionally, all tissue-based neutrophilic responses to fungal infections necessitate contact with the extracellular matrix (ECM). Neutrophils undergo a rapid, ECM-dependent mechanism of homotypic aggregation and NETosis in response to C. albicans mediated by the β2 integrin, complement receptor 3 (CR3, CD11b/CD18, αMβ2). Neither homotypic aggregation nor NETosis occurs when human neutrophils are exposed either to immobilized fungal β-glucan or to C. albicans hyphae without ECM. The current study provides a mechanistic basis to explain how matrix controls the antifungal effector functions of neutrophils under conditions that preclude phagocytosis. We show that CR3 ligation initiates a complex mechanism of integrin cross-talk resulting in differential regulation of the β1 integrins VLA3 (α3β1) and VLA5 (α5β1). These β1 integrins control distinct antifungal effector functions in response to either fungal β-glucan or C. albicans hyphae and fibronectin, with VLA3 inducing homotypic aggregation and VLA5 regulating NETosis. These integrin-dependent effector functions are controlled temporally whereby VLA5 and CR3 induce rapid, focal NETosis early after binding fibronectin and β-glucan. Within minutes, CR3 undergoes inside-out auto-activation that drives the downregulation of VLA5 and the upregulation of VLA3 to support neutrophil swarming and aggregation. Forcing VLA5 to remain in the activated state permits NETosis but prevents homotypic aggregation. Therefore, CR3 serves as a master regulator during the antifungal neutrophil response, controlling the affinity states of two different β1 integrins, which in turn elicit distinct effector functions.

Footnotes

  • This work was supported by National Institutes of Health Grants GM066194 (J.S.R.), HL125265 (J.S.R. and M.K.), and DK106512, HL109582, and DK084195 (V.G.) and by United Negro College Fund/Merck Graduate Science Research Dissertation Fellowships (A.S.B. and C.M.J.). Work was also supported by funds from the Department of Surgery, Rhode Island Hospital.

  • Received November 9, 2015.
  • Accepted October 20, 2016.
  • Copyright © 2016 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 209 (1)
The Journal of Immunology
Vol. 209, Issue 1
1 Jul 2022
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Integrin Cross-Talk Regulates the Human Neutrophil Response to Fungal β-Glucan in the Context of the Extracellular Matrix: A Prominent Role for VLA3 in the Antifungal Response
Courtney M. Johnson, Xian M. O’Brien, Angel S. Byrd, Valentina E. Parisi, Alex J. Loosely, Wei Li, Hadley Witt, Hafeez M. Faridi, Craig T. Lefort, Vineet Gupta, Minsoo Kim, Jonathan S. Reichner
The Journal of Immunology November 16, 2016, 1502381; DOI: 10.4049/jimmunol.1502381

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Integrin Cross-Talk Regulates the Human Neutrophil Response to Fungal β-Glucan in the Context of the Extracellular Matrix: A Prominent Role for VLA3 in the Antifungal Response
Courtney M. Johnson, Xian M. O’Brien, Angel S. Byrd, Valentina E. Parisi, Alex J. Loosely, Wei Li, Hadley Witt, Hafeez M. Faridi, Craig T. Lefort, Vineet Gupta, Minsoo Kim, Jonathan S. Reichner
The Journal of Immunology November 16, 2016, 1502381; DOI: 10.4049/jimmunol.1502381
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