Abstract
Clinically, severe bacterial infection can cause septicemia and multiple organ dysfunction syndrome, especially liver injury. CD38 is closely related to many inflammatory pathways, but its role in liver injury caused by bacterial infection remains unclear. The purpose of this study is to discuss the specific role of CD38 in bacterial liver injury. Eight-week-old male C57BL/6 mice (WT, CD38−/− and CD38−/−TLR4mut) were used and stimulated with Escherichia coli (ATCC25922) or PBS, intraperitoneally. After 3 hours of bacterial stimulation, serum was collected to detect ALT and AST concentration, and liver tissue was harvested for hematoxylin and eosin staining and bacterial culture. The mRNA expressions of TLR4, NLRP3, IL-1β, IL-18, and GSDMD were quantitatively determined by RT-qPCR. The expressions of TLR4, MyD88, TRIF, NF-κB p65, NLRP3, GSDMD, and cytokines were detected by Western blot. The expression and localization of ERK1/2 were detected by immunohistochemistry and Western blot. The results showed that bacterial stimulation could upregulate the expression of inflammatory cytokines, leading to hepatic dysfunction. Moreover, bacterial stimulation of CD38-deficient mice can aggravate the inflammatory response, the expressions of TLR4, NF-κB, and ERK1/2 were significantly increased, and the biomarkers related to pyroptosis also manifested more obvious pyroptosis. However, TLR4 mutation significantly alleviated inflammation and pyroptosis in the liver caused by bacteria, on the basis of CD38 deficiency. Overall, CD38 knockout exacerbates bacteria-induced liver damage through TLR4-NLRP3-GSDMD-mediated pyroptosis.
Highlights
Severe bacterial infection can cause septicemia, and sepsis has been recognized as a global health priority by WHO because of the current estimates of 30 million episodes and six million deaths per year [1]
In the liver of Cluster of differentiation 38 (CD38)-/TLR4mut mice, the pathological changes of the above were obviously relieved (Figures 2(h)–2(k)). These results show that E. coli can cause more serious liver injury in CD38-/mice than in WT mice, and the loss of CD38 will aggravate the damage of bacteria to the liver, but Toll-like receptor 4 (TLR4) mutation can reduce liver injury in septicemia aggravated by CD38 deletion
We found that CD38 deletion stimulated by E. coli can aggravate the inflammatory response of mice through the TLR4-nuclear factor-κB (NF-κB) p65 pathway
Summary
Severe bacterial infection can cause septicemia, and sepsis has been recognized as a global health priority by WHO because of the current estimates of 30 million episodes and six million deaths per year [1]. The lifethreatening organ dysfunction caused by dysregulated host response to infection is a thorny issue in sepsis [2], including liver injury, one of the main clinical manifestations and an independent risk factor for multiple organ dysfunction syndrome (MODS) and high mortality rate in patients with sepsis [3]. The study has shown that liver injury due to sepsis was shown to be induced via oxidative damage, inflammatory response, and neutrophil infiltration [5] and hepatic pathology in sepsis mainly includes steatosis, cholangiolitis, intrahepatic cholestasis, periportal inflammation, and apoptosis [6]. Cluster of differentiation 38 (CD38), a type II transmembrane protein, is the major ADP-ribosyl cyclase in mammals, which is a key NAD+-dependent enzyme [8]. CD38 is a multifunctional transmembrane protein that is widely expressed in immune cells [9], controls the innate
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