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Review
. 2018 Nov;48 Suppl 2(Suppl 2):e12964.
doi: 10.1111/eci.12964. Epub 2018 Jun 22.

Calcium signalling and related ion channels in neutrophil recruitment and function

Roland Immler  1 , Scott I Simon  2 , Markus Sperandio  1
Affiliations
Review

Calcium signalling and related ion channels in neutrophil recruitment and function

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.

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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.
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