Crosstalk between efferocytic myeloid cells and T-cells and its relevance to atherosclerosis.

The interplay between myeloid cells and T-lymphocytes is critical to the regulation of host defense and inflammation resolution. Dysregulation of this interaction can contribute to the development of chronic inflammatory diseases. Important among these diseases is atherosclerosis, which refers to focal lesions in the arterial intima driven by elevated apolipoprotein B-containing lipoproteins, notably low-density lipoprotein (LDL), and characterized by the formation of a plaque composed of inflammatory immune cells, a collection of dead cells and lipids called the necrotic core, and a fibrous cap. As the disease progresses, the necrotic core expands, and the fibrous cap becomes thin, which increases the risk of plaque rupture or erosion. Plaque rupture leads to a rapid thrombotic response that can give rise to heart attack, stroke, or sudden death. With marked lowering of circulating LDL, however, plaques become more stable and cardiac risk is lowered-a process known as atherosclerosis regression. A critical aspect of both atherosclerosis progression and regression is the crosstalk between innate (myeloid cells) and adaptive (T-lymphocytes) immune cells. Myeloid cells are specialized at clearing apoptotic cells by a process called efferocytosis, which is necessary for inflammation resolution. In advanced disease, efferocytosis is impaired, leading to secondary necrosis of apoptotic cells, inflammation, and, most importantly, defective tissue resolution. In regression, efferocytosis is reawakened aiding in inflammation resolution and plaque stabilization. Here, we will explore how efferocytosing myeloid cells could affect T-cell function and vice versa through antigen presentation, secreted factors, and cell-cell contacts and how this cellular crosstalk may contribute to the progression or regression of atherosclerosis.

Low MBOAT7 expression, a genetic risk for MASH, promotes a profibrotic pathway involving hepatocyte TAZ upregulation.

BACKGROUND AND AIMS: The common genetic variant rs641738 C>T is a risk factor for metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASH), including liver fibrosis, and is associated with decreased expression of the phospholipid-remodeling enzyme MBOAT7 (LPIAT1). However, whether restoring MBOAT7 expression in established metabolic dysfunction-associated steatotic liver disease dampens the progression to liver fibrosis and, importantly, the mechanism through which decreased MBOAT7 expression exacerbates MASH fibrosis remain unclear. APPROACH AND RESULTS: We first showed that hepatocyte MBOAT7 restoration in mice with diet-induced steatohepatitis slows the progression to liver fibrosis. Conversely, when hepatocyte-MBOAT7 was silenced in mice with established hepatosteatosis, liver fibrosis but not hepatosteatosis was exacerbated. Mechanistic studies revealed that hepatocyte-MBOAT7 restoration in MASH mice lowered hepatocyte-TAZ (WWTR1), which is known to promote MASH fibrosis. Conversely, hepatocyte-MBOAT7 silencing enhanced TAZ upregulation in MASH. Finally, we discovered that changes in hepatocyte phospholipids due to MBOAT7 loss-of-function promote a cholesterol trafficking pathway that upregulates TAZ and the TAZ-induced profibrotic factor Indian hedgehog (IHH). As evidence for relevance in humans, we found that the livers of individuals with MASH carrying the rs641738-T allele had higher hepatocyte nuclear TAZ, indicating higher TAZ activity and increased IHH mRNA. CONCLUSIONS: This study provides evidence for a novel mechanism linking MBOAT7-LoF to MASH fibrosis, adds new insight into an established genetic locus for MASH, and, given the druggability of hepatocyte TAZ for MASH fibrosis, suggests a personalized medicine approach for subjects at increased risk for MASH fibrosis due to inheritance of variants that lower MBOAT7.

Efferocytosis in liver disease.

The process of dead cell clearance by phagocytic cells, called efferocytosis, prevents inflammatory cell necrosis and promotes resolution and repair. Defective efferocytosis contributes to the progression of numerous diseases in which cell death is prominent, including liver disease. Many gaps remain in our understanding of how hepatic macrophages carry out efferocytosis and how this process goes awry in various types of liver diseases. Thus far, studies have suggested that, upon liver injury, liver-resident Kupffer cells and infiltrating monocyte-derived macrophages clear dead cells, limit inflammation, and, through macrophage reprogramming, repair liver damage. However, in unusual settings, efferocytosis can promote liver disease. In this review, we will focus on efferocytosis in various types of acute and chronic liver diseases, including metabolic dysfunction-associated steatohepatitis. Understanding the mechanisms and consequences of efferocytosis by hepatic macrophages has the potential to shed new light on liver disease pathophysiology and to guide new treatment strategies to prevent disease progression.

Hepatocyte-targeted siTAZ therapy lowers liver fibrosis in NASH diet-fed chimeric mice with hepatocyte-humanized livers.

Nonalcoholic steatohepatitis (NASH) is emerging as the most common cause of liver disease. Although many studies in mouse NASH models have suggested therapies, translation to humans is poor, with no approved drugs for NASH. One explanation may lie in differences between mouse and human hepatocytes. We used NASH diet-fed chimeric mice reconstituted with human hepatocytes (hu-liver mice) to test a mechanism-based hepatocyte-targeted small interfering RNA (siRNA), GalNAc-siTaz, shown previously to block the progression to fibrotic NASH in mice. Following ablation of endogenous hepatocytes, male mice were reconstituted with human hepatocytes from a single donor with the rs738409-C/G PNPLA3 risk variant, resulting in ∼95% human hepatocyte reconstitution. The mice were then fed a high-fat choline-deficient l-amino acid-defined diet for 6 weeks to induce NASH, followed by six weekly injections of GalNAc-siTAZ to silence hepatocyte-TAZ or control GalNAc-siRNA (GalNAc-control) while still on the NASH diet. GalNAc-siTAZ lowered human hepatic TAZ and IHH, a TAZ target that promotes NASH fibrosis. Most important, GalNAc-siTAZ decreased liver inflammation, hepatocellular injury, hepatic fibrosis, and profibrogenic mediator expression versus GalNAc-control, indicating that GalNAc-siTAZ decreased the progression of NASH in mice reconstituted with human hepatocytes. In conclusion, silencing TAZ in human hepatocytes suppresses liver fibrosis in a hu-liver model of NASH.