3′mRNA sequencing reveals pro-regenerative properties of c5ar1 during resolution of murine acetaminophen-induced liver injury

Abstract

Murine acetaminophen-induced acute liver injury (ALI) serves as paradigmatic model for drug-induced hepatic injury and regeneration. As major cause of ALI, acetaminophen overdosing is a persistent therapeutic challenge with N-acetylcysteine clinically used to ameliorate parenchymal necrosis. To identify further treatment strategies that serve patients with poor N-acetylcysteine responses, hepatic 3′mRNA sequencing was performed in the initial resolution phase at 24 h/48 h after sublethal overdosing. This approach disclosed 45 genes upregulated (≥5-fold) within this time frame. Focusing on C5aR1, we observed in C5aR1-deficient mice disease aggravation during resolution of intoxication as evidenced by increased liver necrosis and serum alanine aminotransferase. Moreover, decreased hepatocyte compensatory proliferation and increased caspase-3 activation at the surroundings of necrotic cores were detectable in C5aR1-deficient mice. Using a non-hypothesis-driven approach, herein pro-regenerative/-resolving effects of C5aR1 were identified during late acetaminophen-induced ALI. Data concur with protection by the C5a/C5aR1-axis during hepatectomy and emphasize the complex role of inflammation during hepatic regeneration and repair.

Targeting cathepsin C ameliorates murine acetaminophen-induced liver injury

“…The spleen displays a context-specific regulatory potential that may affect course and consequences of systemic inflammation 41 . In order to characterize splenic gene expression during the evolving resolution phase of APAP intoxication 16 , mice were exposed to APAP for 30 h. Thereafter, serum ALT (Figure 1 A), hepatic Cxcl2 gene expression (Figure 1 B), the hepatic Cxcl2/ALT relationship (Figure 1 C) as well as splenic Cxcl2 (Figure 1 D) and TNFα (Figure 1 E) gene expression were determined to verify liver injury and local/systemic inflammation. Absence of splenic Cxcl2 (Figure 1 D) and TNFα (Figure 1 E) gene induction indicates lack of manifest systemic inflammation at this interface time point (30 h) connecting hepatic injury and initial resolution/regeneration 16 .…”

“…In order to characterize splenic gene expression during the evolving resolution phase of APAP intoxication 16 , mice were exposed to APAP for 30 h. Thereafter, serum ALT (Figure 1 A), hepatic Cxcl2 gene expression (Figure 1 B), the hepatic Cxcl2/ALT relationship (Figure 1 C) as well as splenic Cxcl2 (Figure 1 D) and TNFα (Figure 1 E) gene expression were determined to verify liver injury and local/systemic inflammation. Absence of splenic Cxcl2 (Figure 1 D) and TNFα (Figure 1 E) gene induction indicates lack of manifest systemic inflammation at this interface time point (30 h) connecting hepatic injury and initial resolution/regeneration 16 . Upregulation of hepatic Cxcl2 expression correlated (R 2 = 0.6969, p < 0.0001) with liver damage detected by ALT (Figure 1 B-C) which reflects ongoing local necroinflammation after APAP overdosing.…”

“…International Publisher cytokines such as interleukin (IL)-17 [8,9], IL-18 [10,11], and interferon (IFN)-γ [12,13] are consistently found to contribute to APAP-mediated liver pathology. On the other hand, current data likewise suggest that inflammation can support the resolution of APAP-induced acute liver injury (ALI) [7,14], for example by activating pro-regenerative hepatocyte signaling through IL-6 [15] and C5a/C5aR1 [16]. This dichotomy also extends to the function of neutrophils which have been reported to promote hepatic injury during APAP intoxication [17,18], for example by serving as a source of pathogenic IFNγ [19].…”

Immunomodulatory Activity and Its Mechanisms of Two Polysaccharides from Poria cocos

“…Salmon 1.10.2 software was initially used to count transcripts, and tximport was used to process Salmon’s estimated read counts per transcript [ 40 ]. The rlog function from the DESeq2 (version: 1.28.1) package was used to transform the read counts from the RNA-seq alignment, and the DEseq2 method was used to identify genes with differential expression [ 41 ].…”