The Role of Innate Immune Cells in Nonalcoholic Steatohepatitis

Abstract

Inflammation and metabolic dysfunction are hallmarks of nonalcoholic steatohepatitis (NASH), which is one of the fastest‐growing liver diseases worldwide. Emerging evidence indicates that innate immune mechanisms are pivotal drivers of inflammation and other pathological manifestations observed in NASH, such as hepatosteatosis, insulin resistance (IR), and fibrosis. This robust innate immune reaction is intrinsic to the liver, which is an important immunological organ that contains a coordinated network of innate immune cells, including Kupffer cells (KCs), dendritic cells (DCs), and lymphocytes. Hepatocytes and liver sinusoidal endothelial cells (LSECs) are not formally innate immune cells, but they take on immune cell function when stressed. These cells can sense excess metabolites and bacterial products and translate those signals into immune responses and pathological hepatic changes during the development of NASH. In this review, we take a historical perspective in describing decades of research that aimed to identify the key molecular and cellular players in the innate immune system in the setting of NASH. Furthermore, we summarize the innate immune cells that are involved in the progression of NASH and illustrate how they sense disturbances in circulating metabolic factors by innate immune receptors and subsequently initiate the intercellular signaling cascades that lead to persistent inflammation and progression of hepatic complications.

Human translatability of the GAN diet-induced obese mouse model of non-alcoholic steatohepatitis

“…Chronic hepatic inflammation represents a major driver for development of NASH and is considered one of the strongest independent predictors for progression into fibrosis [45]. In agreement with aberrant innate and adaptive immune responses in NASH pathology [46,47], GAN DIO-NASH mice showed gene regulations within both immune systems. Gene markers for monocyte recruitment, migration and activation were most consistently upregulated in GAN DIO-NASH mice, suggesting that increased abundance of pro-inflammatory macrophages play an important role in this model.…”

Innate lymphocytes: pathogenesis and therapeutic targets of liver diseases and cancer

“…135 Almost all cells in the liver are involved in NAFLD pathogenesis, including hepatocytes, LSECs, HSCs, KCs, monocytes, neutrophils, DCs, T cells, B cells, and other innate lymphocytes. 136 cNK cells were found to be recruited into the liver in a CXCL10dependent manner, and they prevented NASH progression to fibrosis through the production of IFN-γ, which regulated macrophage polarization toward M1-like macrophages. 137,138 IL-15 signaling in hepatocytes upregulated the expression of chemokines CXCL10, CCL2, and CCL5, accounting for the recruitment of immune cells, including NK cells, into the liver.…”

Neutrophils in liver diseases: pathogenesis and therapeutic targets

“…Preexisting diseases, including obesity, type 2 diabetes, hyperlipidemia, and insulin resistance, are regarded as the major risk factors for the development of NAFLD. 22 Hepatic steatosis is a common consequence of hepatic injury in response to alcohol, toxins, chemotherapy, or metabolic syndrome with insulin resistance and has become the most common liver disease worldwide, including in China. [23][24][25] Hepatic steatosis can progress to NASH, which is characterized by inflammation and metabolic disorders.…”