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Immunoregulatory Role of NK Cells in Tissue Inflammation and Regeneration

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Review

Immunoregulatory Role of NK Cells in Tissue Inflammation and Regeneration

Annie Tosello-Trampont et al. Front Immunol.

Abstract

NK cells represent an important first line of defense against viral infection and cancer and are also involved in tissue homeostasis. Studies of NK cell activation in the last decade have revealed that they are able to respond to the inflammatory stimuli evoked by tissue damage and contribute to both progression and resolution of diseases. Exacerbation of the inflammatory response through interactions between immune effector cells facilitates the progression of non-alcoholic fatty liver disease (NAFLD) into steatosis, cirrhosis, and hepatocellular carcinoma (HCC). When hepatic damage is incurred, macrophage activation is crucial for initiating cross talk with neighboring cells present in the liver, including hepatocytes and NK cells, and the importance of this interaction in shaping the immune response in liver disease is increasingly recognized. Inflicted structural damage can be in part regenerated via the process of self-limiting fibrosis, though persistent hepatic damage will lead to chronic fibrosis and loss of tissue organization and function. The cytotoxic activity of NK cells plays an important role in inducing hepatic stellate cell apoptosis and thus curtailing the progression of fibrosis. Alternatively, in some diseases, such as HCC, NK cells may become dysregulated, promoting an immunosuppressive state where tumors are able to escape immune surveillance. This review describes the current understanding of the contributions of NK cells to tissue inflammation and metabolic liver diseases and the ongoing effort to develop therapeutics that target the immunoregulatory function of NK cells.

Keywords: NK cells; fibrosis; immunoregulation; liver; regeneration.

Figures

Figure 1
Figure 1
In the context of viral infection or fatty liver disease, NK cells can be stimulated via their activating receptors or by toll-like receptors (TLRs) that recognize pathogen-associated molecular patterns and DAMPs expressed by injured cells. During liver injury-induced inflammation, NK cells are able to regulate inflammatory (M1) and anti-inflammatory (M2) macrophages depending on the phase of the immune response and stage of disease.
Figure 2
Figure 2
Suppression of NK cell-derived IFN-γ production is mediated by CD33+CD11bloHLA-DRlo myeloid-derived suppressor cells (MDSCs) following a reduction in available arginine via an Arg-1 mechanism. During HCV infection, HCV core protein induces MDSC development. Following the loss of arginine, the mTOR pathway is unable to efficiently translate IFN-γ mRNA, and the subsequent loss of IFN-γ protein production and secretion from NK cells in the liver results in immune evasion by HCV.
Figure 3
Figure 3
The activation stage of HSCs can influence the ability of NK cells to exert cytotoxic activity. While quiescent HSCs are resistant to apoptotic signals, their activation leads to increased surface expression of TRAIL-R. Following engagement of their activating receptors, NK cells can conduct cytotoxic activity by releasing lytic granules or by transduction of death signals through death receptor/ligand interactions (i.e., TRAIL/TRAIL-R, FasL/Fas). Fully activated HSCs expressing Timp-1 are protected from apoptosis. These HSCs can differentiate into myofibroblasts that produce large amounts of fibrous proteins, which can lead to fibrosis when not restrained. ECM, extracellular matrix.

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