B cell survival and development is dependent on the coordination of NFkappaB family members RelB and cRel
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE62559 | GEO | 2015/10/16
SECONDARY ACCESSION(S): PRJNA264412
REPOSITORIES: GEO
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Project description:Targeted deletion of BAFF causes severe deficiency of splenic B cells. BAFF-R is commonly thought to signal to nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase dependent noncanonical NF-κB RelB. However, RelB-deficient mice have normal B-cell numbers. Recent studies showed that BAFF also signals to the canonical NF-κB pathway, and we found that both RelB and cRel are persistently activated, suggesting BAFF signaling coordinates both pathways to ensure robust B-cell development. Indeed, we report now that combined loss of these 2 NF-κB family members leads to impaired BAFF-mediated survival and development in vitro. Although single deletion of RelB and cRel was dispensable for normal B-cell development, double knockout mice displayed an early B-cell developmental blockade and decreased mature B cells. Despite disorganized splenic architecture in Relb(-/-)cRel(-/-) mice, generation of mixed-mouse chimeras established the developmental phenotype to be B-cell intrinsic. Together, our results indicate that BAFF signals coordinate both RelB and cRel activities to ensure survival during peripheral B-cell maturation.
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Project description:NF-kB is a transcriptional factor that consists in homo and heterodimers of the large family of Rel subunits. Among the most important functions for NF-kB, initiation of immunological/inflammatory responses and regulation of cell proliferation/apoptosis which are the major features of severe infections. Although the role of NF-kB is crucial in host defense against pathogens, mice deficient for individual subunits of NF-kB have not been explored in murine models of polymicrobial infection. In this report, we have investigated in vivo the consequences of cRel subunit deficiency in the survival to polymicrobial infection. We have also approached the underlying mechanisms of the host defense by analyzing cytokine production, bacterial clearance and the distribution of innate and adaptive immune cells. Absence of cRel enhances mice mortality to polymicrobial sepsis. The decreased survival of cRel-/- animals upon infection is not related to altered local mechanisms of innate defense such as the peritoneal recruitment of the Gr.1+CD11b+ phagocytic cells and the bacterial clearance. However, cRel deficiency allows to altered systemic cytokine response associated to sustained loss of the lymphoïd subset CD8a+ of spleen dendritic cells, key antigen-presenting cells for the initiation of the adaptive immunity. Genome-wide analysis of the systemic host response to polymicrobial sepsis reveals inflammatory/immune and apoptotic gene signatures associated to cRel subunit. In this study we identified the NF-kB member cRel, as a key factor which plays a critical role in survival to polymicrobial sepsis and also as a regulatory transcription subunit controlling the inflammatory and the adaptive immune responses in severe infection.
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Project description:NF-kB plays a crucial role in immunity to infection. This transcription factor consists in different combinatory homo- and hetero-dimers of the five members of the Rel family. cRel/p50-containing dimers have been involved in the development and function of the immune cells. However, the transcriptional roles of these two subunits still remain poorly explored in innate immune cells. By a multiple approach integrating ex vivo genomic analysis and an in vivo experimental study, we have investigated the consequences of the combined absence of cRel and p50 subunits of NF-kB in the innate response to infection. We have performed gene profiling of cRel-/-p50-/- (DKO) and wild type (WT) peritoneal macrophages stimulated with endotoxin for 2, 6 or 18 hours.
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