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Review
. 2022 Jun 25;11(13):2025.
doi: 10.3390/cells11132025.

Integrin Regulators in Neutrophils

Sunitha Pulikkot  1 , Liang Hu  2 , Yunfeng Chen  3   4 , Hao Sun  5 , Zhichao Fan  1
Affiliations
Review

Integrin Regulators in Neutrophils

Sunitha Pulikkot et al. Cells. .

Abstract

Neutrophils are the most abundant leukocytes in humans and are critical for innate immunity and inflammation. Integrins are critical for neutrophil functions, especially for their recruitment to sites of inflammation or infections. Integrin conformational changes during activation have been heavily investigated but are still not fully understood. Many regulators, such as talin, Rap1-interacting adaptor molecule (RIAM), Rap1, and kindlin, are critical for integrin activation and might be potential targets for integrin-regulating drugs in treating inflammatory diseases. In this review, we outline integrin activation regulators in neutrophils with a focus on the above critical regulators, as well as newly discovered modulators that are involved in integrin activation.

Keywords: RIAM; Rap1; integrins; kindlin; neutrophils; talin.

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Conflict of interest statement

No conflict of interest, financial or otherwise, are declared by the authors.

Figures

Figure 1
Figure 1
Schematic of neutrophil recruitment cascade: Flowing neutrophils roll on vascular endothelial cells through the interaction between PSGL-1 and selectins. Engagement of PSGL-1 with selectins induces the extension of LFA-1, which binds ICAM-1 or other ligands with an intermediate affinity and slows down rolling velocity. We call this process slow rolling. β1 Integrins are also involved in neutrophil rolling and slow rolling. When rolling neutrophils encounter chemokines, LFA-1 or Mac-1 will be fully activated and bind ICAM-1 or other ligands with a high affinity and stop rolling neutrophils. We call this process arrest. After arrest, neutrophils spread and crawl on endothelial cells, which is predominantly mediated by Mac-1. Neutrophils undergo trans-endothelial migration in an LFA-1/Mac-1-dependent manner to the tissue or site of injury. Created in BioRender.com (accessed on 12 June 2022).
Figure 2
Figure 2
Schematic of the integrin activation conformational changes and key modulators: Resting integrins have a bent low-affinity (E−H−) conformation. They attain an extended low-affinity (E+H−) confirmation through the RIAM- and Rap1-mediated recruitment of talin-1. Further recruitment of kindlin-3 induces full integrin activation into extended high-affinity integrins (E+H+). There is an alternative allosteric pathway in which E−H− integrins transition to a bent-high affinity conformation (E−H+) and then change to an extended high-affinity integrin (E+H+). Which integrin adaptors are involved in this allosteric pathway remains to be further investigated. Created in BioRender.com (accessed on 12 June 2022).
Figure 3
Figure 3
Schematics showing domains and binding proteins of talin (A), RIAM (B), and kindlin (C). Integrin-NPXY: Asn-Pro-x-Tyr motifs of the β-integrin tail; Integrin MP region: membrane-proximal region of the β-integrin tail; Integrin-NxxY/F: Asn-x-x-Tyr/Phe motifs of the β-integrin tail; PIP2: phosphatidylinositol 4,5-bisphosphate; PIP3: phosphatidylinositol-3,4,5-triphosphate; Profilin-Actin: direct binding to profilin and indirect binding to actin. Created in BioRender.com (accessed on 12 June 2022).
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