Calcium signalling and related ion channels in neutrophil recruitment and function - PubMed (original) (raw)

Review

. 2018 Nov;48 Suppl 2(Suppl 2):e12964.

doi: 10.1111/eci.12964. Epub 2018 Jun 22.

Affiliations

Review

Roland Immler et al. Eur J Clin Invest. 2018 Nov.

Abstract

The recruitment of neutrophils to sites of inflammation, their battle against invading microorganisms through phagocytosis and the release of antimicrobial agents is a highly coordinated and tightly regulated process that involves the interplay of many different receptors, ion channels and signalling pathways. Changes in intracellular calcium levels, caused by cytosolic Ca2+ store depletion and the influx of extracellular Ca2+ via ion channels, play a critical role in synchronizing neutrophil activation and function. In this review, we provide an overview of how Ca2+ signalling is initiated in neutrophils and how changes in intracellular Ca2+ levels modulate neutrophil function.

Keywords: CRAC channels; Orai1; P2X receptors; SOCE; STIM1; TRP channels; calcium channels; calcium signalling; leucocyte recruitment cascade; neutrophil; potassium channels.

© 2018 Stichting European Society for Clinical Investigation Journal Foundation.

PubMed Disclaimer

Figures

Figure 1

Figure 1. Calcium signaling cascade in neutrophils

(A) Store operated calcium entry (SOCE) can be initiated either via activation of Fcγ-receptors (FcγRs), β2-integrins, the engagement of P-selectin glycoprotein ligand 1 (PSGL-1) and L-selectin with E-selectin expressed on inflamed endothelium, or via G-protein coupled receptors (GPCRs). Activation of GPCRs leads to dissociation of the G-protein subunits α and βγ and subsequent activation of phospholipase (PLC) β. FcγRs, β2-integrins and PSGL-1/L-selectin signaling in turn, activate PLCγ involving spleen tyrosine kinase (Syk). Both, activated PLCβ and PLCγ convert phosphatidylinositol 4,5 bisphosphate (PIP2) into diacylglycerol (DAG) and inositol-1,4,5 triphosphate (IP3). IP3 binds to and opens the IP3 receptor (IP3R) in the membrane of the endoplasmic reticulum (ER) which results in Ca2+ flux out of the ER into the cytoplasm via IP3R. Upon store depletion, the Ca2+ sensor stromal interaction molecule 1 (STIM1) translocates to PM-ER-junctions and activates Orai1, the predominant Ca2+ release activated Ca2+ (CRAC) channel in neutrophils. This allows the entry of extracellular Ca2+ into the neutrophil, exerting a variety of functions, including (B) phagocytosis, ROS production, secretion and degranulation of vesicles, activation of β2-integrins and cytoskeletal rearrangement leading to polarization and migration.

Figure 2

Figure 2. Calcium signaling functions to synchronize events in neutrophil recruitment

Neutrophil rolling via PSGL-1, L-selectin, and E-selectin causes downstream activation of IP3R and subsequent release of ER stored Ca2+, which in turn shifts LFA-1 from a low to an intermediate and high affinity state. This shift leads to deceleration of the rolling neutrophil via LFA-1-ICAM-1 interaction. The activation of GPCRs by chemokines further increases intracellular Ca2+ levels via IP3R. Additionally, GPCR signaling via DAG activates additional LFA-1 which increases the number of LFA-1/ICAM-1 bonds, resulting in total arrest of the neutrophil (inside-out signaling). High affinity LFA-1 binding to ICAM-1 further enhances rise in intracellular Ca2+ concentrations (outside-in signaling), amplified by shear forces. Upon force transduction, Kindlin-3 binds to β2-integrin tails, recruits Orai1 and thus forms a complex which ensures increase in Ca2+ levels directly at focal adhesion spots, a process again highly dependent on shear forces to orient cell polarization and migration. This is followed by clustering of LFA-1 and the recruitment of Talin1 which links the focal adhesion spots to the cytoskeleton, enabling intraluminal crawling of the neutrophil.

Similar articles

Cited by

References

    1. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13:159–175. - PubMed
    1. Sperandio M, Gleissner Ca, Ley K. Glycosylation in immune cell trafficking. Immunol Rev. 2009;230:97–113. - PMC - PubMed
    1. Morikis VA, et al. Selectin catch-bonds mechanotransduce integrin activation and neutrophil arrest on inflamed endothelium under shear flow. Blood. 2017;130:2101–2110. - PMC - PubMed
    1. Mueller H, et al. Tyrosine kinase Btk regulates E-selectin-mediated integrin activation and neutrophil recruitment by controlling phospholipase C (PLC) γ2 and PI3Kγ pathways. Blood. 2010;115:3118–3127. - PMC - PubMed
    1. Pruenster M, et al. Extracellular MRP8/14 is a regulator of β2 integrin-dependent neutrophil slow rolling and adhesion. Nat Commun. 2015;6:6915. - PMC - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources