Higher Monocyte Expression of TLR2 and TLR4, and Enhanced Pro-inflammatory Synergy of TLR2 with NOD2 Stimulation in Sarcoidosis

Sarcoidosis is an inflammatory disease of unknown etiology. However, an infectious cause has been proposed suggesting a role for pattern-recognition receptors, such as Toll-like receptors (TLRs) and nucleotide-binding domain, leucin-rich repeat containing family proteins (NLRs), in the pathogenesis. Our aim was to investigate whether differences in TLR2 and TLR4 expression, and the response to TLR2, TLR4, and NOD2 stimulation, are associated with sarcoidosis. Blood mononuclear cells from sarcoidosis patients (n = 24) and healthy subjects (n = 19) were incubated with the TLR2 ligands PGN and Pam3CSK4, the TLR4 ligand LPS, the NOD2 ligand MDP, or medium alone. After 16 h, monocyte TLR2 and TLR4 expression and cytokine secretion, including TNF alpha, IL-1 beta, IL-6, IL-8, IL-10, and IL-12p70, were measured using flow cytometry and cytometric bead array. TLR2 and TLR4 expression at baseline was significantly higher in patients. Combined TLR2 and NOD2 stimulation induced a four-fold higher secretion of TNF alpha and a 13-fold higher secretion of IL-1 beta in patients. Additionally, there was a synergistic effect of TLR2 with NOD2 stimulation on induction of IL-1 beta in patients, whereas IL-10 was synergistically induced in healthy subjects. Increased TLR expression and enhanced secretion of pro-inflammatory cytokines after combined TLR2 and NOD2 stimulation may be related to the pathogenesis of sarcoidosis.