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Published on: September 24, 2011
Chemokines, selectins and intracellular calcium flux: temporal and spatial cues for leukocyte arrest
1Department of Biomedical Engineering, Graduate Group in Immunology, University of California, Davis CA, USA.
Insights
Leukocyte recruitment relies on precise signaling cues. Calcium flux, regulated by CRAC channels like Orai1, is crucial for activating integrins and enabling leukocyte migration to injury sites.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Leukocyte trafficking is vital for immune responses, requiring precise adhesion and migration to injury or infection sites.
- Chemokines like IL-8 guide leukocyte movement by activating integrins for firm adhesion.
- G-protein coupled receptor (GPCR) signaling is essential for cytoskeletal changes and cell polarization during migration.
Purpose of the Study:
- To investigate the role of intracellular calcium (Ca2+) flux in leukocyte recruitment.
- To elucidate how CRAC channels, such as Orai1, contribute to Ca2+ signaling during leukocyte adhesion and polarization.
- To highlight calcium's function as a messenger in activating integrins for cell migration.
Main Methods:
- Review of existing literature on leukocyte trafficking, chemokine signaling, and calcium dynamics.
- Analysis of the interplay between selectins, chemokines, and integrins in leukocyte adhesion.
- Focus on the role of CRAC channels and intracellular calcium flux in PMN (polymorphonuclear leukocyte) arrest and polarization.
Main Results:
- Chemokine recognition triggers integrin activation, leading to firm adhesion and migration.
- GPCR signaling mobilizes intracellular calcium, GTPases, and cytoskeletal proteins for cell polarization.
- Intracellular Ca2+ flux, potentially via Orai1, is critical for initiating PMN arrest and polarization.
Conclusions:
- Calcium acts as a key signaling messenger, activating integrin clusters and promoting a migratory phenotype in leukocytes.
- The cooperative signaling between chemokines, selectins, and integrins, under shear stress, is essential for effective leukocyte recruitment.
- Understanding calcium's role offers insights into immune cell migration and potential therapeutic targets.
Abstract:
Leukocyte trafficking to acute sites of injury or infection requires spatial and temporal cues that fine tune precise sites of firm adhesion and guide migration to endothelial junctions where they undergo diapedesis to sites of insult. Many detailed studies on the location and gradient of chemokines such as IL-8 and other CXCR ligands reveal that their recognition shortly after selectin-mediated capture and rolling exerts acute effects on integrin activation and subsequent binding to their ligands on the endothelium, which directs firm adhesion, adhesion strengthening, and downstream migration. In this process, G-protein coupled receptor (GPCR) signaling has been found to play an integral role in activating and mobilizing intracellular stores of calcium, GTPases such as Rap-1 and Rho and cytokeletal proteins such as Talin and F-actin to facilitate cell polarity and directional pseudopod formation. A critical question remaining is how intracellular Ca(2+) flux from CRAC channels such as Orai1 synergizes with cytosolic stores to mediate a rapid flux which is critical to the onset of PMN arrest and polarization. Our review will highlight a specific role for calcium as a signaling messenger in activating focal clusters of integrins bound to the cytoskeleton which allows the cell to attain a migratory phenotype. The precise interplay between chemokines, selectins, and integrins binding under the ubiquitous presence of shear stress from blood flow provides an essential cooperative signaling mechanism for effective leukocyte recruitment.
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