New kid on the block: Netrin‐1 as a novel player in the delicate molecular network of hepatic inflammation

Liver inflammation is a key characteristic of most chronic liver diseases (CLDs), which are estimated to affect more than one billion people worldwide and thus represent a substantial global burden. [1] Liver inflammation may be caused by a large range of genetic, metabolic, toxic, or viral factors, which is evident by the plethora of etiologies of inflammatory liver diseases including infection with HBV or HCV, alcoholic liver disease, NASH, and NAFLD. Hepatocyte proliferation, hepatocyte survival, and extracellular matrix accumulation are affected by hepatic inflammation, leading to chronic fibrosis and eventually cirrhosis. [2] Ultimately, patients with CLD causing fibrosis or cirrhosis are at risk of organ failure or development of HCC. Hepatic macrophages are key players in inflammationrelated events in the liver, and different types of macrophages have been shown to exhibit proinflammatory or antiinflammatory functions. Hepatic macrophages are broadly separated into residing macrophages, also named Kupffer cells, and monocytederived macrophages; but both can be subdivided further based on marker expression and functional role. [3] Upon inflammation, monocytederived macrophages extravasate into the injured liver in a chemokine (CC motif) ligand 2 (CCL2)– dependent manner, become cluster of differentiation 45– positive (CD45+) CD11b+ F4/80low lymphocyte antigen 6 complex high (Ly6Chi) proinflammatory macrophages, elicit a pronounced immune response, exhibit profibrotic functions, and activate HSCs. [2,4] Therefore, a better understanding of common and distinct molecular mechanisms underlying liver inflammation and progression to CLD is crucial for the development of effective drugs to prevent hepatic inflammation. In this issue of Hepatology, Barnault et al. report that netrin1 (NTN1) protein levels are strongly upregulated in HepaRG cells and in primary human hepatocytes (PHHs) by exposure to tolllike receptor ligands Pam3CysSer(Lys)4, Riboxxol, and polyinosinic:polycytidylic acid (poly[I:C]), which are wellknown initiators of acute hepatic inflammation. [5] In addition, the authors demonstrate that NTN1 expression is regulated posttranscriptionally in both HepaRG cells and PHHs, although by different molecular mechanisms. In HepaRG cells, representing a model of dedifferentiated hepatocytes and of latestage CLD, NTN1 transcripts are bound by the RNAbinding protein Staufen1 (STAU1). STAU1 protein accumulates at the endoplasmic reticulum (ER) upon poly(I:C) treatment, binds directly to the 5′untranslated region of NTN1 transcripts, and promotes the translational induction of NTN1, resulting in increased NTN1 protein levels and secretion of NTN1 (Figure 1). In contrast, NTN1 protein levels are increased after inflammatory stimulation in a STAU1independent manner involving total polysomebased translation of the NTN1 transcript for the final induction of the protein in murine livers and PHHs. [5] Although the mechanisms of NTN1 induction by inflammatory signaling appear to be molecularly different in dedifferentiated HepaRG cells and PHHs, both converge in the rapid induction of NTN1 secretion. In mouse experiments, poly(I:C) treatment induced NTN1 expression and production of key inflammatory cytokines such as CCL2, CCL3, CCL5, and CCL8. However, the humanized antiNTN1 antibody NP137[6] was able to prevent the induction of inflammatory gene expression and reduced the number of Ly6C+ intrahepatic macrophages under inflammatory conditions in vivo. [5] Thus, the antiNTN1 antibody NP137 is a promising candidate for the treatment of patients with chronic hepatic inflammation of different etiologies at risk of developing HCC because NP137 was found to be well tolerated in patients with advanced solid tumors (https://clini caltr ials.gov/ ct2/show/NCT02 977195). Interestingly, NTN1 was found to be overexpressed in several cancers, and functionally, it has been suggested to inhibit apoptosis. Two kinds of NTN1 receptors, deleted in colorectal carcinoma (DCC) and the uncoordinated 5 family of proteins (UNC5A– D), have been demonstrated to transduce proapoptotic signals Received: 25 March 2022 | Accepted: 25 March 2022