The E3 ubiquitin ligase Cblb has a crucial role in the prevention of chronic inflammation and autoimmunity. However, a recent study showed that Cblb also has an unexpected function in acute lung inflammation (81) . Cblb attenuates the sequestration of PMN in the lungs after administration of LPS. In a model of polymicrobial sepsis in which acute lung inflammation depends on TLR4, the loss of Cblb expression accentuates acute lung inflammation and reduces survival. Cblb controls the association between TLR4 and the intracellular adaptor MyD88. Expression of WT Cblb, but not expression of a Cblb mutant that lacks E3 ubiquitin ligase function, prevents the activity of a reporter gene for NF-κB in monocytes that have been challenged with LPS. The downregulation of TLR4 expression on the cell surface of PMN is impaired in the absence of Cblb. These data reveal that Cblb regulates the TLR4mediated acute inflammatory response that is induced by sepsis (81) .