Biology subjects

Mirshahi, F.

Publications and source records attributed to Mirshahi, F..

2 recordsLinked to original sources

bioRxiv2024

Effective anti-tumor immune response against HCC is orchestrated by immune cell partnership network that functions through hepatic homeostatic pathways, not direct cytotoxicity

BackgroundMetabolic dysfunction-associated fatty liver disease (MAFLD) can progress to hepatocellular carcinoma (HCC), yet the immune mechanisms driving this transition remain unclear. MethodsIn a chronic Western diet (WD) mouse model, we performed single-nuclei RNA sequencing to track MAFLD progression into HCC and subsequent tumor inhibition upon dietary correction. ResultsCarcinogenesis begins during MAFLD, with tumor cells entering dormancy when HCC is mitigated. Rather than purely tolerogenic, the liver actively engages immune responses targeting myofibroblasts, fibroblasts and hepatocytes to maintain tissue homeostasis. Cytotoxic cells contribute to turnover of liver cells but do not primarily target the tumor. NKT cells predominate under chronic WD, while monocytes join them in HCC progression on a WD. Upon dietary correction, monocyte-driven immunity confers protection against HCC through targeting tissue homeostatic pathways and antioxidant mechanisms. Crucially, liver tissue response--not merely immune activation--dictates whether tumors grow or regress, emphasizing the importance of restoring liver tissue integrity. Also, protection against HCC is linked to a distinct immunological pattern, differing from healthy controls, underscoring the need for immune reprogramming. ConclusionThese findings reveal the dual roles of similar pathways, where immune patterns targeting different cells shape distinct outcomes. Restoring tissue homeostasis and regeneration creates a tumor-hostile microenvironment, whereas tumor-directed approaches fail to remodel the TME. This underscores the need for tissue remodeling strategies in cancer prevention and treatment. Lay summaryOur study challenges the traditional view that the liver is purely tolerant to immune responses, revealing that it actively regulates immunity to maintain tissue health. We found that liver cancer (HCC) begins during fatty liver disease (MAFLD) but can be halted if immune cells--especially monocytes--restore tissue integrity. Instead of focusing solely on killing tumors, effective immunotherapy should harness the bodys natural ability to repair the liver, creating an environment where cancer cannot thrive. This discovery paves the way for innovative treatments that promote immune-driven tissue regeneration as a strategy for cancer prevention and therapy.

immunology↗

bioRxiv2024

Loss of TIM4-Dependent Efferocytosis in Kupffer CellsPromotes Liver Fibrosis in Nonalcoholic Steatohepatitis

Background and aimsHepatocyte apoptosis is a key feature of non-alcoholic steatohepatitis (NASH), but the fate of apoptotic hepatocytes in NASH is poorly understood. Herein we explore the hypothesis that impaired TIM4-mediated clearance of dead hepatocytes by liver macrophages (efferocytosis) is impaired in NASH and drives the progression to liver fibrosis. MethodsKupffer cell (KC)-TIM4 expression and efferocytosis were assayed in normal and NASH liver from humans and diet-induced NASH mice. The engulfment of human and mouse apoptotic hepatocytes by primary human and mouse liver KCs was assayed ex vivo. Causation was assessed in NASH mice using anti-TIM4 antibodies, KC-TIM4-knockout, or inducible KC-TIM4 expression, with analyses focused on efferocytosis of apoptotic hepatocytes by liver macrophages and liver fibrosis. ResultsIn human and mouse NASH liver, apoptotic hepatocytes accumulated and was associated with the loss of the KC efferocytosis receptor TIM4. Anti-TIM4 inhibited the engulfment of apoptotic hepatocytes by primary human and mouse liver KCs ex vivo, and anti-TIM4 administration to early NASH mice worsened liver macrophage efferocytosis and accelerated the progression to fibrotic NASH. A similar result was obtained by genetically deleting TIM4 in KCs in NASH mice. Most importantly, genetic restoration of macrophage TIM4 in NASH mice enhanced the clearance of apoptotic hepatocytes by liver macrophages and decreased liver fibrosis. ConclusionsThe loss of macrophage TIM4 that occurs during NASH progression impairs the clearance of apoptotic hepatocytes by liver macrophages, which subsequently promotes the progression to fibrotic NASH. This pathogenic sequence of events can be prevented by restoring macrophage TIM4, suggesting that future therapeutic approaches designed to boost TIM4 expression in liver macrophages could represent a novel strategy to prevent fibrotic NASH progression. Lay summaryNonalcoholic steatohepatitis (NASH) is emerging as the leading cause of liver disease, but the processes leading to liver fibrosis in NASH, which determines clinical outcome, are incompletely understood. Our study provides evidence impaired clearance of dead liver cells by liver macrophages in NASH, which is due to loss of a macrophage receptor called TIM4, contributes to liver fibrosis. Knowledge of this process may suggest new ways to bolster the clearance of dead liver cells in NASH and thereby prevent the progression to liver fibrosis and subsequent liver disease.

pathology↗