Mannan-Binding Lectin Suppresses Peptidoglycan-Induced TLR2 Activation and Inflammatory Responses

Abstract

Peptidoglycan (PGN), as the major components of the bacterial cell wall, is known to cause excessive proinflammatory cytokine production. Toll-like receptor 2 (TLR2) is abundantly expressed on immune cells and has been shown to be involved in PGN-induced signaling. Although more and more evidences have indicated that PGN is recognized by TLR2, the role of TLR2 PGN recognition is controversial. Mannan-binding lectin (MBL), a plasma C-type lectin, plays a key role in innate immunity. More and more evidences show that MBL could suppress the amplification of inflammatory signals. Whether MBL can alter PGN-elicited cellular responses through TLR2 in macrophages is still unknown, and possible mechanism underlying it should be investigated. In this study, we found that MBL significantly attenuated PGN-induced inflammatory cytokine production, including TNF-α and IL-6, in PMA-stimulated THP-1 cells at both mRNA and protein levels. The expression of TLR2 was strongly induced by PGN stimulation. Furthermore, the administration of TLR2-neutralized antibody effectively suppressed PGN-induced TNF-α and IL-6 expression. These results supplied the evidence that PGN from Saccharomyces cerevisiae could be recognized by TLR2. In addition, we also found that MBL decreased PGN-induced TLR2 expression and suppressed TLR2-mediated downstream signaling, including the phosphorylation of IκBα, nuclear translocation of NF-κBp65, and phosphorylation of MAPK p38 and ERK1/2. Administration of MBL alone did not have an effect on the expression of TLR2. Finally, our data showed that PGN-mediated immune responses were more severely suppressed by preincubation with MBL and indicated that MBL can combine with both TLR2 and PGN to block the inflammation cytokine expression induced by PGN. All these data suggest that MBL could downregulate inflammation by modulating PGN/TLR2 signaling pathways. This study supports an important role for MBL in immune regulation and signaling pathways involved in inflammatory responses.

Mannan-Binding Lectin Attenuates Inflammatory Arthritis Through the Suppression of Osteoclastogenesis

“…In the present study, we investigated the role of the p38 signaling pathway in RANKL-treated precursors in the presence of MBL protein, and have demonstrated that MBL has an inhibitory effect on osteoclast differentiation via downregulation of the p38/c-fos/NFATc1 signaling pathways. The result is consistent with several other observations showing that the regulation of monocytes activation and macrophage polarization by MBL under the inflammatory condition was associated with repression of p38 signaling pathway (45, 46).…”

Role of Protein Glycosylation in Host-Pathogen Interaction

“…The β-glucan on F. monophora cell wall can trigger the host lectin Dectin-1 on the surface of dendritic cells (DCs). Then Dectin-1 activates the transcription factor interferon regulatory factor 1 (IRF1), which is vital for IL-12A transcription, and consequently triggers T H 1 and T H 17 immune responses against the fungus [40,223,224]. However, in this process, the human mincle on the surface of DCs is simultaneously triggered by the pathogen via proper carbohydrate molecule(s).…”

Mannose-binding lectin reduces oxidized low-density lipoprotein induced vascular endothelial cells injury by modulating autophagy via LOX1

“…MBL also participates in the modulation of in ammation. A previous study reported that MBL could attenuate peptidoglycan induced in ammatory cytokine production and suppress nuclear translocation of NF-κBp65, phosphorylation of IκBα, MAPK p38, and ERK1/2 [33]. MBL may also inhibit autoreactive T cells' activation and proliferation via cell surface calreticulin in patients with silicosis [34].…”