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Attenuated viral hepatitis in Trem1-/- mice is associated with reduced inflammatory activity of neutrophils
Jan-Hendrik Kozik1, Tanja Trautmann1, Antonella Carambia1
1University Medical Centre Hamburg-Eppendorf, Department of Medicine I, 20246 Hamburg, Germany.
Abstract:
TREM1 (Triggering Receptor Expressed on Myeloid Cells 1) is a pro-inflammatory receptor expressed by phagocytes, which can also be released as a soluble molecule (sTREM1). The roles of TREM1 and sTREM1 in liver infection and inflammation are not clear. Here we show that patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection manifest elevated serum levels of sTREM1. In mice, experimental viral hepatitis induced by infection with Lymphocytic Choriomeningitis Virus (LCMV)-WE was likewise associated with increased sTREM1 in serum and urine, and with increased TREM1 and its associated adapter molecule DAP12 in the liver. Trem1-/- mice showed accelerated clearance of LCMV-WE and manifested attenuated liver inflammation and injury. TREM1 expression in the liver of wild-type mice was mostly confined to infiltrating neutrophils, which responded to LCMV by secretion of CCL2 and TNF-α, and release of sTREM1. Accordingly, the production of CCL2 and TNF-α was decreased in the livers of LCMV-infected Trem1-/- mice, as compared to LCMV-infected wildtype mice. These findings indicate that TREM1 plays a role in viral hepatitis, in which it seems to aggravate the immunopathology associated with viral clearance, mainly by increasing the inflammatory activity of neutrophils.
Insights
Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) exacerbates liver inflammation and injury during viral hepatitis. Blocking TREM1 in mice accelerated viral clearance and reduced liver damage, suggesting a therapeutic target.
Area of Science:
- Immunology
- Hepatology
- Virology
Background:
- Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) is a pro-inflammatory receptor found on phagocytes.
- Soluble TREM1 (sTREM1) can be released into circulation.
- The specific roles of TREM1 and sTREM1 in viral liver infections remain largely unknown.
Purpose of the Study:
- To investigate the role of TREM1 and sTREM1 in viral hepatitis.
- To determine the impact of TREM1 on liver inflammation and injury during viral infections.
Main Methods:
- Analysis of serum sTREM1 levels in patients with Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infections.
- Induction of experimental viral hepatitis in mice using Lymphocytic Choriomeningitis Virus (LCMV)-WE.
- Assessment of TREM1, sTREM1, and DAP12 expression in infected mice.
- Comparison of viral clearance, liver inflammation, and injury in wild-type and Trem1-/- mice.
- Analysis of neutrophil-derived inflammatory mediators (CCL2, TNF-α) in the liver.
Main Results:
- Elevated serum sTREM1 levels were observed in patients with HBV and HCV.
- LCMV-WE infection in mice led to increased sTREM1 in serum and urine, and increased TREM1/DAP12 in the liver.
- Trem1-/- mice exhibited faster LCMV-WE clearance and reduced liver inflammation and injury.
- TREM1 expression in wild-type mouse livers was primarily on neutrophils, which secreted CCL2 and TNF-α upon LCMV infection.
- CCL2 and TNF-α production was diminished in the livers of LCMV-infected Trem1-/- mice.
Conclusions:
- TREM1 plays a significant role in the immunopathology of viral hepatitis.
- TREM1 appears to worsen liver inflammation and injury during viral clearance, primarily by enhancing neutrophil inflammatory activity.
- TREM1 may represent a potential therapeutic target for managing viral hepatitis.
