We identify herein a novel signaling function of the Toll-like receptor-4 (TLR4), the lipopolysaccharide (LPS) receptor mediating the innate immune response, in inducing the expression of CD11b/CD18 integrin in polymorphonuclear leukocytes (PMNs). Studies were made in PMNs isolated from TLR4-deficient (TLR4^-/-) and C57BL/6 (WT) mice. We observed increased CD11b expression in WT PMNs within 3 hr after LPS challenge, whereas CD11b was not expressed in TLR4^-/- PMNs above basal levels. TLR4-activated CD11b expression was cycloheximide-sensitive and involved the activation of transcription factors, NF-B and c-Jun/PU.1. TLR4^-/- PMNs challenged with LPS were functionally defective as the result of the impaired CD11b expression in that they failed to adhere and did not migrate across endothelial cells in response to fMLP. TLR4 also promoted increased binding of LPS to PMNs on the basis expression of CD11b. Thus, TLR4 signaling activates synthesis and upregulation of CD11b and is essential for PMN adhesion and transmigration. Our data suggest an important role of TLR4-activated CD11b expression in the mechanism of the PMN host-defense response to LPS.