Editors' ChoiceInnate Immunity

β3 Integrin as a Coreceptor for TLR2

Science Signaling  24 Jun 2008:
Vol. 1, Issue 25, pp. ec232
DOI: 10.1126/scisignal.125ec232

Toll-like receptor 2 (TLR2) is one of a family of TLRs involved in recognition of pathogenic molecular motifs. TLR2 signaling is specifically activated by bacterial lipoproteins, such as LTA (lipoteichoic acid) and zymosan, and can be activated by synthetic bacterial lipopeptides (BLPs) consisting of tri- or di-palmitoyl-S-glycerylcysteine and a short peptide, but not mono-acylated peptides. Gerold et al. found that human monocytes (THP-1 cells) produced more inflammatory cytokine in response to the triacylated BLP(SK4) in the presence of serum than in the absence, and, with a version of BLP(SK4) modified with a crosslinker and affinity tags, identified vitronectin as the serum protein responsible for this enhanced response. Priming THP-1 cells with a phorbol ester increased the transcription and abundance of the β3 integrin subunit, which is the receptor for vitronectin, and primed cells plated on vitronectin, but not other extracellular matrix proteins, showed enhanced cytokine production in response to BLP(SK4), as well as to the TLR2 ligands LTA and zymosan, and the TLR4 ligand LPS. Blocking β3 integrin with either function-blocking antibodies or with a snake venom protein inhibited BLP(SK4)-mediated stimulation of cytokine production. When β3 integrin was knocked down with shRNA, the cells produced much less cytokine in response to BLP(SK4); however, the response to LPS, which activates TLR4, was not affected. Cells from patients with Glanzmann thrombasthenia, which have mutations in the ITGA2B gene encoding the integrin α2b or ITGB3 encoding the β3 integrin, lacked β3 on the surface and did not produce cytokines in response to BLP(SK4), suggesting that integrin β3 is essential for TLR2 signaling. β3 was coimmunoprecipitated with TLR2 from THP-1 cells, and BLP(SK4) disrupted this interaction and appeared to destabilize β3, as it became undetectable shortly after stimulation. The authors suggest that vitronectin presents pathogen lipopeptides to a complex of β3 integrin and TLR2, which activates TLR2 and disrupts the complex.

G. Gerold, K. A. Ajaj, M. Bienert, H.-J. Laws, A. Zychlinsky, J. L. de Diego, A Toll-like receptor 2-integrin β3 complex senses bacterial lipopeptides via vitronectin. Nat. Immunol. 9, 761-768 (2008). [PubMed]