Mincle suppresses Toll-like receptor 4 activation

Abstract

Regulation of Toll-like receptor responses is critical for limiting tissue injury and autoimmunity in both sepsis and sterile inflammation. We found that Mincle, a C-type lectin receptor, regulates proinflammatory Toll-like receptor 4 signaling. Specifically, Mincle ligation diminishes Toll-like receptor 4-mediated inflammation, whereas Mincle deletion or knockdown results in marked hyperresponsiveness to lipopolysaccharide in vitro, as well as overwhelming lipopolysaccharide-mediated inflammation in vivo. Mechanistically, Mincle deletion does not up-regulate Toll-like receptor 4 expression or reduce interleukin 10 production after Toll-like receptor 4 ligation; however, Mincle deletion decreases production of the p38 mitogen-activated protein kinase-dependent inhibitory intermediate suppressor of cytokine signaling 1, A20, and ABIN3 and increases expression of the Toll-like receptor 4 coreceptor CD14. Blockade of CD14 mitigates the increased sensitivity of Mincle(-/-) leukocytes to Toll-like receptor 4 ligation. Collectively, we describe a major role for Mincle in suppressing Toll-like receptor 4 responses and implicate its importance in nonmycobacterial models of inflammation.

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).…”

“…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). In both studies, this enhanced susceptibility was attributed to increased levels of the TLR4 coreceptor CD14 in Dectin-1-or Mincledeficient mice.…”

Mincle activation enhances neutrophil migration and resistance to polymicrobial septic peritonitis

“…Of note, Greco et al . recently showed the downregulation of TLR4 signaling by Mincle36. Therefore, Mincle could reduce GRK2 expression in sepsis both directly and indirectly by downregulating TLR4 signaling.…”

C-Type Lectin-Like Receptors: Head or Tail in Cell Death Immunity

“…MINCLE is expressed by antigen-presenting cells including macrophages, neutrophils, DCs and B cells (76). Its expression is induced by several inflammatory stimuli and stresses, such as lipopolysaccharide (LPS), tumor necrosis factor (TNF), IL-6 and saturated fatty acids (76)(77)(78)(79) and was found over-expressed in numerous inflammatory diseases (77,(80)(81)(82)(83)(84)(85)(86). Interestingly, a polymorphism in this receptor has been linked to protection against rheumatoid arthritis in humans (87).…”

“…Alternatively, as neutrophils also express MINCLE, the use of antibodies may have exerted pleotropic effects by directly targeting or depleting neutrophils (98). Although MINCLE contributes to inflammation and immunity to contain the insult and initiate tissue repair, it can amplify collateral tissue damage and was therefore demonstrated to be implicated in numerous inflammatory diseases such as obesity, rheumatoid arthritis, allergic contact dermatitis, ischemic stroke, traumatic brain injury, hepatitis, sepsis, and multiple sclerosis (77,(80)(81)(82)(83)(84)(85)(86). Besides, MINCLE recognizes cholesterol crystals abundantly present in atherosclerotic plaques, triggering in macrophages the production of pro-inflammatory molecules (91).…”