Abstract
Integrin-mediated adhesion is a crucial step in lymphocyte extravasation and homing. We show here that not only the chemokines CXCL12 and CXCL13 but also the lysophospholipids sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) enhance adhesion of murine follicular and marginal zone B cells to ICAM-1 in vitro. This process involves clustering of integrin LFA-1 and is blocked by pertussis toxin, suggesting that G(i) family G-proteins are involved. In addition, lysophospholipid-induced adhesion on ICAM-1 depends on Rho and Rhokinase, indicative of an involvement of G(12)/G(13), possibly also G(q)/G(11) family G-proteins. We used G(12)/G(13)- or G(q)/G(11)-deficient B cells to study the role of these G-protein families in lysophospholipid-induced adhesion and found that the pro-adhesive effects of LPA and S1P are completely abrogated in G(12)/G(13)-deficient marginal zone B cells, reduced in G(12)/G(13)-deficient follicular B cells, and normal in G(q)/G(11)-deficient B cells. We also show that loss of lysophospholipid-induced adhesion results in disinhibition of migration in response to the follicular chemokine CXCL13, which might contribute to the abnormal localization of splenic B cell populations observed in B cell-specific G(12)/G(13)-deficient mice in vivo. Taken together, this study shows that lysophospholipids regulate integrin-mediated adhesion of splenic B cells to ICAM-1 through G(i) and G(12)/G(13) family G-proteins but not through G(q)/G(11).
Highlights
In leukocytes, chemokines and their G-protein coupled receptors (GPCRs)2 play an important role in the regulation of integrin activity
Tel.: 49-6221-548255; Fax: 49-6221-548549; E-mail: Nina.Wettschureck@urz.uni-heidelberg.de. 2 The abbreviations used are: GPCR, G-protein coupled receptor; MZ B, marginal zone B; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; PTX, pertussis toxin; S1P, sphingosine 1-phosphate; LPA, lysophosphatidic acid; FITC, fluorescein isothiocyanate; PBS, phosphate-buffered saline; TRITC, tetramethylrhodamine isothiocyanate; chemokine receptors in lymphocyte homing to lymph nodes and PeyerЈs patches [1, 2], not much is known about the regulation of B lymphocyte adhesion in the spleen
To test whether GPCR activation contributes to B cell adhesion in vitro, we incubated murine splenic lymphocytes on ICAM-1- or VCAM-1-coated dishes in the presence or absence of different GPCR agonists and determined the percentage of adherent follicular B or MZ B cells, respectively
Summary
Chemokines and their G-protein coupled receptors (GPCRs) play an important role in the regulation of integrin activity. Treatment with pertussis toxin (PTX), which ADP-ribosylates and thereby inactivates Gi family G-proteins, causes displacement of both follicular B cells and MZ B cells from their physiological niches [5, 7], suggesting that Gi-coupled receptors normally contribute to splenic B cell homing This hypothesis is strengthened by the finding that numbers of MZ B cells are low in mice lacking either the G␣i2 subunit of Gi [8] or different effector molecules of the Gi family like Pyk-2, Rac, or Dock2 [7, 9, 10]. Gi family G-proteins and through the G12/13/Rho/Rho-kinase signaling pathway, while Gq/11 family G-proteins are not involved
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