Mincle Signaling Promotes Con A Hepatitis

Abstract

Concanavalin-A (Con-A) hepatitis is regarded as a T cell-mediated model of acute liver injury. Mincle is a C-type lectin receptor (CLR) that is critical in the immune response to mycobacteria and fungi, but does not have a well-defined role in pre-clinical models of non-pathogen mediated inflammation. Since Mincle can ligate the cell death ligand SAP130, we postulated that Mincle signaling drives intrahepatic inflammation and liver injury in Con-A hepatitis. Acute liver injury was assessed in the murine Con-A hepatitis model using C57BL/6, Mincle−/−, and Dectin-1−/− mice. The role of C/EBPβ and HIF-1α signaling was assessed using selective inhibitors. We found that Mincle was highly expressed in hepatic innate inflammatory cells and endothelial cells in both mice and humans. Furthermore, sterile Mincle ligands and Mincle signaling intermediates were increased in the murine liver in Con-A hepatitis. Most significantly, Mincle deletion or blockade protected against Con-A hepatitis whereas Mincle ligation exacerbated disease. Bone marrow chimeric and adoptive transfer experiments suggested that Mincle signaling in infiltrating myeloid cells dictates disease phenotype. Conversely, signaling via other CLRs did not alter disease course. Mechanistically, we found that Mincle blockade decreased the NF-κβ related signaling intermediates, C/EBPβ and HIF-1α, both of which are necessary in macrophage-mediated inflammatory responses. Accordingly, Mincle deletion lowered production of nitrites in Con-A hepatitis and inhibition of both C/EBPβ and HIF1-α reduced the severity of liver disease. Our work implicates a novel innate immune driver of Con-A hepatitis and, more broadly, suggests a potential role for Mincle in diseases governed by sterile inflammation.

Preliminary exploration of the potential of spliceosome‐associated protein 130 for predicting disease severity in Crohn's disease

“…SAP130 was recently demonstrated to be a novel and promising marker for nonpathogen‐mediated hepatitis and neuroinflammation . Normally, it is located in the nucleus in live cells, but it is released into the extracellular milieu to mediate inflammation response during cellular stress or cell death.…”

“…A mouse model of subarachnoid hemorrhage induced by endovascular perforation showed similar results, and these effects eventually lead to blood–brain barrier disruption and neuronal dysfunction. Furthermore, SAP130 and its receptor Mincle are upregulated in acute liver injury induced by concanavalin A in mice, and SAP130–Mincle signaling induces liver inflammation by modulating expression of crucial proinflammatory and regulatory chemokines via the transcription factors C/EBPβ and HIF‐1α . Increased release of SAP130 is found in a mouse model of alcoholic liver disease, and SAP130 exacerbates alcohol‐induced liver injury by inducing inflammasome‐mediated production of inflammatory cytokines …”

“…SAP130 was recently demonstrated to be a novel and promising marker for nonpathogen-mediated hepatitis and neuroinflammation. [14][15][16][17][18][19] Normally, it is located in the nucleus in live cells, but it is released into the extracellular milieu to mediate inflammation response during cellular stress or cell death. de Rivero et al 19 have identified increased expression of SAP130 and Mincle in cortical neurons after traumatic brain injury in both humans and rodents.…”

“…10,11 It specifically binds to the Mincle (macrophage-inducible C-type lectin, CLEC4E) receptor, which is a transmembrane PRR expressed on innate immune cells, including macrophages, dendritic cells, and neutrophils, and initiates the Fc receptor common γ-chain (FcRγ)spleen tyrosine kinase (Syk) signaling axis to transduce downstream signals, resulting in a potent inflammatory response. [11][12][13] Studies have shown that apparent SAP130 release is associated with acute or chronic hepatitis, such as concanavalin A hepatitis and alcohol-induced liver injury, [14][15][16] and neuroinflammation, such as subarachnoid hemorrhage and traumatic brain injury. [17][18][19] Consequently, this suggests that SAP130 might act as an alarmin for excessive cell death and be involved in innate immune response under conditions of sterile inflammation.…”

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).…”