| First Author | Hwang IY | Year | 2019 |
| Journal | J Immunol | Volume | 203 |
| Issue | 9 | Pages | 2401-2414 |
| PubMed ID | 31548329 | Mgi Jnum | J:280957 |
| Mgi Id | MGI:6370344 | Doi | 10.4049/jimmunol.1900678 |
| Citation | Hwang IY, et al. (2019) Biased S1PR1 Signaling in B Cells Subverts Responses to Homeostatic Chemokines, Severely Disorganizing Lymphoid Organ Architecture. J Immunol 203(9):2401-2414 |
| abstractText | Ligand-engaged chemoattractant receptors trigger Galphai subunit nucleotide exchange, stimulating the activation of downstream effector molecules. Activated chemoattractant receptors also dock G protein-coupled receptor kinases (GRKs) that help mediate receptor desensitization. In this study, we show that the B cell-specific loss of GRK2 severely disrupts B cell trafficking and immune cell homeostasis. The GRK2 deficiency in developing murine B cells leads to a severe immune phenotype, including a major reduction of bone marrow IgD(+) cells, splenomegaly with a loss of white pulp and grossly expanded red pulp, a deficit of Peyer patches, and small lymph nodes with marked reductions in B cell numbers. The major phenotypes in these mice arise from excessive S1PR1 signaling combined with inadequate homeostatic chemokine receptor signaling. CXCL13 signaling is the most severely compromised. In B cells, our data also indicate that S1PR1 signals constitutively, as blocking S1PR1 signaling with an S1PR1 antagonist enhanced CXCL13-triggered wild-type B cell migration. Furthermore, blocking S1PR1 signaling in the GRK2-deficient B cells partially corrected their poor response to chemokines. Treating mice lacking GRK2 expression in their B cells with an S1PR1 antagonist partially normalized B cell trafficking into lymph node and splenic follicles. These findings reveal the critical interdependence of Galphai-linked signaling pathways in controlling B lymphocyte trafficking. |
