| First Author | Sasaki Y | Year | 2018 |
| Journal | J Immunol | Volume | 200 |
| Issue | 10 | Pages | 3438-3449 |
| PubMed ID | 29654209 | Mgi Jnum | J:261488 |
| Mgi Id | MGI:6155503 | Doi | 10.4049/jimmunol.1701526 |
| Citation | Sasaki Y, et al. (2018) Crucial Role of Linear Ubiquitin Chain Assembly Complex-Mediated Inhibition of Programmed Cell Death in TLR4-Mediated B Cell Responses and B1b Cell Development. J Immunol 200(10):3438-3449 |
| abstractText | Linear ubiquitin chain assembly complex (LUBAC)-mediated linear polyubiquitin plays crucial roles in thymus-dependent and -independent type II Ab responses and B1 cell development. In this study, we analyzed the role of LUBAC in TLR-mediated B cell responses. A mouse strain in which LUBAC activity was ablated specifically in B cells (B-HOIP(Deltalinear) mice) showed defective Ab responses to a type I thymus-independent Ag, NP-LPS. B cells from B-HOIP(Deltalinear) mice (HOIP(Deltalinear) B cells) underwent massive cell death in response to stimulation of TLR4, but not TLR9. TLR4 stimulation induced caspase-8 activation in HOIP(Deltalinear) B cells; this phenomenon, as well as TLR4-induced cell death, was suppressed by ablation of TRIF, a signal inducer specific for TLR4. In addition, LPS-induced survival, proliferation, and differentiation into Ab-producing cells of HOIP(Deltalinear) B cells were substantially restored by inhibition of caspases together with RIP3 deletion, but not by RIP3 deletion alone, suggesting that LPS stimulation kills HOIP(Deltalinear) B cells by apoptosis elicited via the TRIF pathway. Further examination of the roles of cell death pathways in B-HOIP(Deltalinear) mice revealed that deletion of RIP3 increased the number of B1 cells, particularly B1b cells, in B-HOIP(Deltalinear) mice, indicating that B1b cell homeostasis is controlled via LUBAC-mediated suppression of necroptosis. Taken together, the data show that LUBAC regulates TLR4-mediated B cell responses and B1b cell development and/or maintenance by inhibiting programmed cell death. |
