The discriminative capacity of soluble Toll-like receptor (sTLR)2 and sTLR4 in inflammatory diseases

ten Oever, Jaap; Kox, Matthijs; van de Veerdonk, Frank L; Mothapo, Khutso M; Slavcovici, Adriana; Jansen, Tim L; Tweehuysen, Lieke; Giamarellos-Bourboulis, Evangelos J; Schneeberger, Peter M; Wever, Peter C; Stoffels, Monique; Simon, Anna; van der Meer, Jos WM; Johnson, Melissa D; Kullberg, Bart-Jan; Pickkers, Peter; Pachot, Alexandre; Joosten, Leo AB; Netea, Mihai G

Alternatively spliced TLR4 mRNA encodes the soluble form of TLR4 [5] . As such, we did not expect a correlation between the membrane expression of TLR4 and circulating sTLR4. On the contrary, sTLR2 results from posttranslational processing: endocytosis of cell surface receptor is followed by conversion into sTLR2 intracellularly [4] . In previous monocyte stimulation experiments, membrane-bound TLR2 correlated negatively with supernatant sTLR2 [4] . We did not observe the downregulation of cell surface TLR expression on monocytes of individuals during endotoxemia. Possible explanations for this lack of correlation are that (1) monocytes are detected only in very low numbers at 2 hours after LPS injection [27] and this subpopulation may well have a different TLR expression than more active monocytes that have marginated at this time-point; (2) we only examined the expression of TLRs on monocytes (CD14 + ), however, other circulating cell subsets such as neutrophils or platelets also express TLR2 [28, 29] , all potentially contributing to the plasma concentrations of sTLRs; (3) the soluble receptors are derived from an intracellular pool, not directly from the cell surface [4] ; and finally (4) besides being shed, membrane bound TLR is influenced by TLR trafficking between intracellular compartments and the cell membrane [30] .