long-term-intravital-multiphoton-microscopy-imaging-immune-cells

Long Term Intravital Multiphoton Microscopy Imaging of Immune Cells in Healthy and Diseased Liver Using CXCR6.Gfp Reporter Mice

Liver inflammation as a response to injury is a highly dynamic process involving the infiltration of distinct subtypes of leukocytes including monocytes, ...

RWTH University-Hospital Aachen

Hepatocellular carcinoma (HCC) typically occurs in patients with chronic inflammatory liver diseases, such as viral hepatitis or (non-)alcoholic steatohepatitis. Inflammation appears indeed as a crucial factor in hepatocarcinogenesis. Nevertheless, sophisticated animal models and studies of human samples revealed that the HCC also elicits antitumor immune responses. Patrolling and infiltrating lymphocytes (e.g., NKT and T cells, respectively) can exert decisive functions in the transition from chronic hepatic inflammation to cancer as well as in antitumor immune responses. An improved understanding of the cellular and molecular mechanisms whereby inflammation promotes or restricts hepatocarcinogenesis will open new avenues for therapeutic approaches to liver cancer.

Role of lymphocytes in liver cancer.

Macrophage activation by bacterial lipopolysaccharides (LPS) is induced through Toll-like receptor 4 (TLR4). The synthesis and activity of TLR4 downstream signaling molecules modulates the expression of pro- and anti-inflammatory cytokines. To address the impact of post-transcriptional regulation on that process, we performed RIP-Chip analysis. Differential association of mRNAs with heterogeneous nuclear ribonucleoprotein K (hnRNP K), an mRNA-specific translational regulator in differentiating hematopoietic cells, was studied in noninduced and LPS-activated macrophages. Analysis of interactions affected by LPS revealed several mRNAs encoding TLR4 downstream kinases and their modulators. We focused on transforming growth factor-β-activated kinase 1 (TAK1) a central player in TLR4 signaling. HnRNP K interacts specifically with a sequence in the TAK1 mRNA 3' UTR in vitro. Silencing of hnRNP K does not affect TAK1 mRNA synthesis or stability but enhances TAK1 mRNA translation, resulting in elevated TNF-α, IL-1β, and IL-10 mRNA expression. Our data suggest that the hnRNP K-3' UTR complex inhibits TAK1 mRNA translation in noninduced macrophages. LPS-dependent TLR4 activation abrogates translational repression and newly synthesized TAK1 boosts macrophage inflammatory response.

Translation control of TAK1 mRNA by hnRNP K modulates LPS-induced macrophage activation.

An overdose of acetaminophen (N-acetyl-p-aminophenol, APAP), also termed paracetamol, can cause severe liver damage, ultimately leading to acute liver failure (ALF) with the need of liver transplantation. APAP is rapidly taken up from the intestine and metabolized in hepatocytes. A small fraction of the metabolized APAP forms cytotoxic mitochondrial protein adducts, leading to hepatocyte necrosis. The course of disease is not only critically influenced by dose of APAP and the initial hepatocyte damage, but also by the inflammatory response following acetaminophen-induced liver injury (AILI). As revealed by mouse models of AILI and corresponding translational studies in ALF patients, necrotic hepatocytes release danger-associated-molecular patterns (DAMPs), which are recognized by resident hepatic macrophages, Kupffer cell (KC), and neutrophils, leading to the activation of these cells. Activated hepatic macrophages release various proinflammatory cytokines, such as TNF-α or IL-1β, as well as chemokines (e.g., CCL2) thereby further enhancing inflammation and increasing the influx of immune cells, like bone-marrow derived monocytes and neutrophils. Monocytes are mainly recruited via their receptor CCR2 and aggravate inflammation. Infiltrating monocytes, however, can mature into monocyte-derived macrophages (MoMF), which are, in cooperation with neutrophils, also involved in the resolution of inflammation. Besides macrophages and neutrophils, distinct lymphocyte populations, especially γδ T cells, are also linked to the inflammatory response following an APAP overdose. Natural killer (NK), natural killer T (NKT) and T cells possibly further perpetuate inflammation in AILI. Understanding the complex interplay of immune cell subsets in experimental models and defining their functional involvement in disease progression is essential to identify novel therapeutic targets for human disease.

Article	Year
Role of lymphocytes in liver cancer. Oncoimmunology\| PubMed ID: 24498546	2013
Translation control of TAK1 mRNA by hnRNP K modulates LPS-induced macrophage activation. RNA (New York, N.Y.)\| PubMed ID: 24751651	2014
Immune mechanisms in acetaminophen-induced acute liver failure. Hepatobiliary surgery and nutrition\| PubMed ID: 25568858	2014

Jana C. Mossanen

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