Macrophages are tissue-resident or infiltrated immune cells critical for innate immunity, normal tissue development, homeostasis, and repair of damaged tissue. Macrophage function is a sum of their ontogeny, the local environment in which they reside, and the type of injuries or pathogen to which they are exposed. In this Review, we discuss the role of macrophages in the restoration of tissue function after injury, highlighting important questions about how they respond to and modify the local microenvironment to restore homeostasis.

/pdf/the-role-of-macrophages-in-the-resolution-of-inflammation-452wo0kz6j.pdf

The role of macrophages in the resolution of inflammation

TWEAK, a member of the tumour necrosis factor superfamily, is a multifunctional cytokine that acts on cells by binding to a small cell-surface receptor named Fn14. Here, Winkles summarizes the biology of the TWEAK–Fn14 axis and describes the recent evidence supporting the notion that this axis could be a therapeutic target for the treatment of cancer, chronic autoimmune diseases and acute ischaemic stroke. TWEAK is a multifunctional cytokine that controls many cellular activities including proliferation, migration, differentiation, apoptosis, angiogenesis and inflammation. TWEAK acts by binding to Fn14, a highly inducible cell-surface receptor that is linked to several intracellular signalling pathways, including the nuclear factor-κB (NF-κB) pathway. The TWEAK–Fn14 axis normally regulates various physiological processes, in particular it seems to play an important, beneficial role in tissue repair following acute injury. Furthermore, recent studies have indicated that TWEAK–Fn14 axis signalling may contribute to cancer, chronic autoimmune diseases and acute ischaemic stroke. This Review provides an overview of TWEAK–Fn14 axis biology and summarizes the available data supporting the proposal that both TWEAK and Fn14 should be considered as potential targets for the development of novel therapeutics.

/pdf/the-tweak-fn14-cytokine-receptor-axis-discovery-biology-and-531r59za07.pdf

The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting.

Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming.

Stem Cells and Liver Regeneration

Loss of Hippo signaling in Drosophila leads to tissue overgrowth as a result of increased cell proliferation and decreased cell death. YAP (a homolog of Drosophila Yorkie and target of the Hippo pathway) was recently implicated in control of organ size, epithelial tissue development, and tumorigenesis in mammals. However, the role of the mammalian Hippo pathway in such regulation has remained unclear. We now show that mice with liver-specific ablation of WW45 (a homolog of Drosophila Salvador and adaptor for the Hippo kinase) manifest increased liver size and expansion of hepatic progenitor cells (oval cells) and eventually develop hepatomas. Moreover, ablation of WW45 increased the abundance of YAP and induced its localization to the nucleus in oval cells, likely accounting for their increased proliferative capacity, but not in hepatocytes. Liver tumors that developed in mice heterozygous for WW45 deletion or with liver-specific WW45 ablation showed a mixed pathology combining characteristics of hepatocellular carcinoma and cholangiocarcinoma and seemed to originate from oval cells. Together, our results suggest that the mammalian Hippo-Salvador pathway restricts the proliferation of hepatic oval cells and thereby controls liver size and prevents the development of oval cell-derived tumors.

https://www.pnas.org/content/pnas/107/18/8248.full.pdf

The Hippo–Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis

Progenitor (“oval”) cell expansion accompanies many forms of liver injury, including alcohol toxicity and submassive parenchymal necrosis as well as experimental injury models featuring blocked hepatocyte replication. Oval cells can potentially become either hepatocytes or biliary epithelial cells and may be critical to liver regeneration, particularly when hepatocyte replication is impaired. The regulation of oval cell proliferation is incompletely understood. Herein we present evidence that a TNF family member called TWEAK (TNF-like weak inducer of apoptosis) stimulates oval cell proliferation in mouse liver through its receptor Fn14. TWEAK has no effect on mature hepatocytes and thus appears to be selective for oval cells. Transgenic mice overexpressing TWEAK in hepatocytes exhibit periportal oval cell hyperplasia. A similar phenotype was obtained in adult wild-type mice, but not Fn14-null mice, by administering TWEAK-expressing adenovirus. Oval cell expansion induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was significantly reduced in Fn14-null mice as well as in adult wild-type mice with a blocking anti-TWEAK mAb. Importantly, TWEAK stimulated the proliferation of an oval cell culture model. Finally, we show increased Fn14 expression in chronic hepatitis C and other human liver diseases relative to its expression in normal liver, which suggests a role for the TWEAK/Fn14 pathway in human liver injury. We conclude that TWEAK has a selective mitogenic effect for liver oval cells that distinguishes it from other previously described growth factors.

/pdf/tweak-induces-liver-progenitor-cell-proliferation-1ceq8ixt3g.pdf

TWEAK induces liver progenitor cell proliferation

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TWEAK induces liver progenitor cell proliferation