Interferon Type I Regulates Inflammasome Activation and High Mobility Group Box 1 Translocation in Hepatocytes During Ehrlichia‐Induced Acute Liver Injury

Abstract

Inflammasomes are an important innate immune host defense against intracellular microbial infection. Activation of inflammasomes by microbial or host ligands results in cleavage of caspase-1 (canonical pathway) or caspase-11 (noncanonical pathway), release of interleukin (IL)-1β, IL-18, high mobility group box 1 (HMGB1), and inflammatory cell death known as pyroptosis. Ehrlichia are obligate, intracellular, gram-negative bacteria that lack lipopolysaccharide but cause potentially life-threatening monocytic ehrlichiosis in humans and mice that is characterized by liver injury followed by sepsis and multiorgan failure. Employing murine models of mild and fatal ehrlichiosis caused by infection with mildly and highly virulent Ehrlichia muris (EM) and Ixodes ovatus Ehrlichia (IOE), respectively, we have previously shown that IOE infection triggers type I interferon (IFN-I) response and deleterious caspase-11 activation in liver tissues, which promotes liver injury and sepsis. In this study, we examined the contribution of IFN-I signaling in hepatocytes (HCs) to Ehrlichia-induced liver injury. Compared to EM infection, we found that IOE enter and replicate in vitro cultured primary murine HCs and induce secretion of IFNβ and several chemokines, including regulated upon activation, normal T-cell expressed, and secreted (RANTES), monocyte chemoattractant protein 1 (MCP1), monokine induced by gamma (MIG)/chemokine (C-X-C motif) ligand 9 (CXCL9), macrophage inflammatory protein 1 alpha (MIP1α), keratinocyte-derived chemokine (KC), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Notably, in vitro stimulation of uninfected and Ehrlichia-infected HCs with recombinant IFNβ triggered activation of caspase-1/11, cytosolic translocation of HMGB1, and enhanced autophagy and intracellular bacterial replication. Secretion of HMGB1 by IOE-infected HCs was dependent on caspase-11. Primary HCs from IOE-but not EM-infected mice also expressed active caspase-1/11. Conclusion: HC-specific IFN-I signaling may exacerbate liver pathology during infection with obligate intracellular Ehrlichia by promoting bacterial replication and detrimental caspase-11-mediated inflammasome activation. (Hepatology Communications 2020;0:1-19).

Leukocyte‐Derived High‐Mobility Group Box 1 Governs Hepatic Immune Responses to Listeria monocytogenes

“…In our analysis, translocation of HMGB1 into the cytoplasm of hepatocytes and high serum HMGB1 levels were exclusively observed during aggravated infection and may be driven by pathogen‐induced signaling, i.e., mediated by interferons. ( 38 ) Importantly, however, hepatocyte‐specific HMGB1 deletion did not affect bacterial burden, hepatic inflammation, or animal survival over a wide range of pathogen concentrations. Our findings thus constitute a remarkable contrast to the important roles of hepatocyte HMGB1 during sterile hepatic necroinflammation ( 13 ) and LPS‐induced shock.…”

STING1 in sepsis: Mechanisms, functions, and implications

“… 54 , 55 Mechanically, type I IFNs could induce HMGB1 release, leading to caspase 11 (CASP11)-dependent pyroptosis in macrophages and hepatocytes, thus mediating bacterial infection-induced lethal coagulation. 56 , 57 Given that sepsis mortality often occurs after a prolonged period of immunosuppression rather than exaggerated inflammation, 58 type I IFNs might play a different role in the later stage of sepsis compared to a role in innate and adaptive immune responses. However, in a low-lethality sepsis model, interferon alpha and beta receptor subunit 1 (IFNAR1)-deficient mice and chimeric mice lacking IFNAR1 in hematopoietic cells display increased mortality after CLP, with elevated peritoneal bacterial counts and reduced C-X-C motif chemokine ligand 10 (CXCL10)-dependent peritoneal neutrophil recruitment and function.…”

Protective Immunity and Immunopathology in Ehrlichiosis

“…The canonical inflammasome pathway involves signaling by the NLRP3 complex, after recognition of PAPMs or DAMPs, via the adaptor molecule ASC; consequently, activation of caspase-1 causes cleavage of pro-IL-1β and pro-IL-18, and the release of biologically active IL-1β and IL-18 [80][81][82][83]. In the non-canonical inflammasome pathway, cytosolic LPS triggers activation of caspase-11, which in turn activates caspase-1 and promotes secretion of IL-18, IL-1β, and HMGB1, as well as inflammatory cell death, known as pyroptosis [84][85][86][87][88]. The gasdermin D protein is essential for caspase-11-dependent pyroptosis [88][89][90][91].…”

“…Thus, the greater susceptibility of caspase 1 -/mice to fatal ehrlichiosis might be due to altered survival of HCs. Unlike caspase 1 -/mice, mice deficient in NLRP3 (Nlrp3 -/mice) effectively clear ehrlichiae on day 7 post infection; however, these mice still exhibit acute mortality and develop liver injury similarly to wild-type mice [84,85]. Notably, the susceptibility of wild-type, caspase 1 -/and NLRP3 -/mice, and the development of liver damage, are associated with higher expression of active caspase 11 in the liver in these mice than in wild type mice.…”