Dectin-1 Regulates Hepatic Fibrosis and Hepatocarcinogenesis by Suppressing TLR4 Signaling Pathways

Abstract

Summary Dectin-1 is a C-type lectin receptor critical in anti-fungal immunity but Dectin-1 has not been linked to regulation of sterile inflammation or oncogenesis. We found that Dectin-1 expression is upregulated in hepatic fibrosis and liver cancer. However, Dectin-1 deletion exacerbates liver fibro-inflammatory disease and accelerates hepatocarcinogenesis. Mechanistically, we found that Dectin-1 protects against chronic liver disease by suppressing TLR4 signaling in hepatic inflammatory and stellate cells. Accordingly, Dectin-1−/− mice exhibited augmented cytokine production and reduced survival in LPS-mediated sepsis whereas Dectin-1 activation was protective. We showed that Dectin-1 inhibits TLR4 signaling by mitigating TLR4 and CD14 expression which are regulated by Dectin-1-dependent M-CSF expression. Our study suggests that Dectin-1 is an attractive target for experimental therapeutics in hepatic fibrosis and neoplastic transformation. More broadly, our work deciphers critical cross-talk between pattern recognition receptors and implicates a role for Dectin-1 in suppression of sterile inflammation, inflammation-induced oncogenesis, and LPS-mediated sepsis.

Contact, Collaboration, and Conflict: Signal Integration of Syk-Coupled C-Type Lectin Receptors

“…Finally, Miller and coworkers (154,155) recently demonstrated an unexpected inhibition of TLR4-dependent inflammatory cytokine expression by the CLR Dectin-1 and Mincle (Fig. 4C).…”

“…4C). First, they observed that Dectin-1-deficient mice showed more hepatic fibrosis in a model of liver inflammation (154). Similarly, Mincle-deficient mice were more susceptible to endotoxic shock than were wild-type controls, resulting in higher mortality and elevated cytokine levels (155).…”

Porphyromonas gingivalis lipopolysaccharide induces over production of CC chemokine ligand 2 via toll‐like receptor‐4 in oral lichen planus

“…In this study, we again confirmed higher CCL2 expression in keratinocytes from OLP patients, compared with that of control subjects, which was reported in our recent study. A few studies demonstrated that TLR‐4‐induced CCL2 overproduction in podocytes, macrophages, hepatic stellate cells, gingival epithelial cells, and even lung cancer cells . In these studies, LPS or another PAMP ligand induced TLR‐4 expression via an independent NF‐κB signaling pathway.…”

The innate immune signaling in cancer and cardiometabolic diseases: Friends or foes?

“…Dectin-1 also enhances NK-dependent tumor cell killing by recognizing the N-glycan structures of some cancer cells and activating IRF5 [136]. It has also recently been reported that Dectin-1 protects against liver fibroinflammatory disease and hepatocarcinogenesis by inhibiting TLR4 signaling [137]. However, the association between cancer and Dectin-2, another important CLR, has not been extensively investigated.…”