Enhanced LPS-induced peritonitis in mice deficiency of cullin 4B in macrophages

Cullin 4B (CUL4B), a member of the cullin protein family, is a scaffold protein of the CUL4B–RING–E3 ligase complex that ubiquitinates intracellular proteins.CUL4B’s targets include cell cycle-regulated proteins and DNA replication-related molecules. In this study, we generated myeloid-specific Cul4b -deficient mice ( Cul4b f/y ;LysM-Cre KI/KI ) to investigate the influence of Cul4b deficiency on innate immunity, especially on the function of macrophages. Our results show that an intraperitoneal injection of lipopolysaccharide (LPS) led to a significant decrease in body weights and increased leukocyte infiltrates with increased chemokines in the peritoneal cavity of Cul4b f/y ;LysM-Cre KI/KI mice. However, the proinflammatory cytokines, IL-6 and TNF-α did not increase in LPS-injected Cul4b f/y ;LysM-Cre KI/KI mice. Furthermore, bone marrow-derived macrophages from Cul4b f/y ;LysM-Cre KI/KI mice secreted higher levels of chemokines but lower levels of TNF-α and IL-6 upon LPS stimulation. Of note, increased proliferation of Cul4b- deficient macrophages was also observed. These results show that myeloid-specific Cul4b deficiency worsens LPS-induced peritonitis. In addition, Cul4b deficiency leads to enhanced DNA replication and proliferation, increased production of chemokines but a decreased production of proinflammatory cytokines of macrophages. Our data highlight a new role of cullin family, CUL4B, in the immune system.