Mannan-binding lectin deficiency exacerbates sterile liver injury in mice through enhancing hepatic neutrophil recruitment

Abstract

Noninfectious liver injury, including the effects of drugs and diet, is a major cause of liver diseases worldwide. The innate inflammatory response to hepatocyte death plays a crucial role in the outcome of liver injury. Mannan-binding lectin (MBL) is a pattern recognition molecule of the innate immune system, which is primarily produced by liver. MBL deficiency occurs with high frequency in the population and is reported associated with predisposition to infectious diseases. We here observed that genetic MBL ablation strongly sensitizes mice to sterile liver injury induced by carbon tetrachloride (CCl 4 ). Aggravated liver damage was shown in CCl 4 -administrated MBL −/− mice, as evidenced by severe hepatocyte death, elevated serum alanine aminotransferase and lactate dehydrogenase activity, and enhanced production of inflammatory cytokines. Mechanistic studies established that MBL deficiency caused increased chemokine CXCL2 production from liver macrophages upon CCl 4 stimulation, thereby promoting the hepatic recruitment of neutrophils and subsequent liver damage. Furthermore, MBL-mediated protection from CCl 4induced liver injury was validated by administration of an MBL-expressing liver-specific adenoassociated virus, which effectively ameliorated the hepatic damage in CCl4-treated MBL -/mice.We propose that MBL may be exploited as a new therapeutic approach in the treatment of chemical-induced sterile liver injury in patients with MBL deficiency. K E Y W O R D Scarbon tetrachloride, CXCL2, mannan-binding lectin, neutrophil, sterile liver injury

Mannan-Binding Lectin Regulates Inflammatory Cytokine Production, Proliferation, and Cytotoxicity of Human Peripheral Natural Killer Cells

“…These results were consistent with our previous finding that exogenous MBL reduces the inflammatory cytokine production of monocytes in vitro [16]. Additionally, we and others found that MBL deficiency elevated the inflammatory cytokines production both in mice [19] and humans [18]. Furthermore, this finding could be explained by an early study suggesting that the binding of MBL to autologous cells is most likely to take place at inflammatory loci, where it rec-ognizes endogenous ligands and induces the release of antiinflammatory mediators [48].…”

“…Indeed, monocyte-derived DC from individuals with MBL deficiency showed an enhanced proinflammatory cytokine production in response to microbial stimulation [18]. Recently, we demonstrated that MBL ablation in mice could exacerbate sterile liver inflammation [19]. The other in vivo study also found that injection of recombinant MBL in mice could regulate the host immune response [20].…”

Status of mannose-binding lectin (MBL) and complement system in COVID-19 patients and therapeutic applications of antiviral plant MBLs

“…Taken together, studies indicate that sMBL is capable of controlling the activity of NK cells and can act as an immune response regulator [93]. Therefore, sMBL is a pleiotropic immune modulator that can influence various cell types of innate and adaptive immunity [93,94].…”

Glucan and Mannan—Two Peas in a Pod

“…The mannose receptor functions in endocytosis and phagocytosis, and is deeply involved in immune homeostasis by scavenging unwanted mannoglycoproteins [18]. Mannan-binding lectin (mannose-binding lectin) participates in the innate immune system and is produced mainly by hepatocytes [24,25].…”

“…Among the other pattern recognition receptors, the mannose receptor is among the best-characterized C-type lectins. It binds mannosyl, fucosyl, or N-acetylglucosamine (GlcNAc)-glycoconjugate ligands on various bacteria, fungi, and parasites to mediate significant inflammatory responses [25]. The mannose receptor also helps to clear glycosylated endogenous ligands.…”