Dynamic Shifts in the Composition of Resident and Recruited Macrophages Influence Tissue Remodeling in NASH

Abstract

SUMMARY Macrophage-mediated inflammation is critical in the pathogenesis of non-alcoholic steatohepatitis (NASH). Here, we describe that, with high-fat, high-sucrose-diet feeding, mature TIM4 pos Kupffer cells (KCs) decrease in number, while monocyte-derived Tim4 neg macrophages accumulate. In concert, monocyte-derived infiltrating macrophages enter the liver and consist of a transitional subset that expresses Cx3cr1/Ccr2 and a second subset characterized by expression of Trem2, Cd63, Cd9 , and Gpmnb ; markers ascribed to lipid-associated macrophages (LAMs). The Cx3cr1/Ccr2 -expressing macrophages, referred to as C-LAMs, localize to macrophage aggregates and hepatic crown-like structures (hCLSs) in the steatotic liver. In C-motif chemokine receptor 2 ( Ccr2 )-deficient mice, C-LAMs fail to appear in the liver, and this prevents hCLS formation, reduces LAM numbers, and increases liver fibrosis. Taken together, our data reveal dynamic changes in liver macrophage subsets during the pathogenesis of NASH and link these shifts to pathologic tissue remodeling.

Hepatic Macrophage Responses in Inflammation, a Function of Plasticity, Heterogeneity or Both?

“…(B) If the inflammatory insult is not resolved (e.g., in case of chronic infection, repeated injury or metabolic stress associated with increased lipid burden), the resolution phase is not reached and chronic inflammation develops. Increased KC death activates the niche cells (LSECs, HSCs and hepatocytes) to call in Ly6C hi monocytes to replenish lost KCs (4,(23)(24)(25)32). Continuous activation and/or tissue injury may lead to death of structural cells of the liver.…”

“…In certain inflammatory settings, such as NASH and fibrosis/cirrhosis, it has recently been shown that these cells express genes including Spp1, Gpnmb (mouse) Trem2 and Cd9 (mouse and human). In mouse, these cells were termed lipid-associated macrophages (LAMs) while in human they were called scar-associated macrophages (SAMs) ( 4 , 30 , 32 ). Alignment of the LAMs and SAMs showed significant overlap ( 4 ) suggesting these could indeed be equivalent populations.…”

Immunometabolism of Tissue-Resident Macrophages – An Appraisal of the Current Knowledge and Cutting-Edge Methods and Technologies

“…This is best exemplified by recent studies of Kupffer cells in mouse models of metabolicassociated fatty liver disease (MAFLD). Intriguingly, Kupffer cell numbers and/or identity is lost during the course of the MAFLD sequelae non-alcoholic steatohepatitis (NASH) (62,150,161,162). These cells are, at least in part, replaced by monocytederived macrophages that appear to seed the liver long-term and assume transcriptional programs similar to those of their longterm TRM counterparts.…”

“…These cells are, at least in part, replaced by monocytederived macrophages that appear to seed the liver long-term and assume transcriptional programs similar to those of their longterm TRM counterparts. This is intriguing because these newcomers, despite exhibiting transcriptional, epigenetic, and functional similarities to their long-lived Kupffer cell counterparts (34,150,161), appear to have different responses to lipids (including triglycerides) and contribute to NASH progression differently (161,162). For instance, on one hand, monocyte-derived liver TRMs appear to less efficiently promote storage of triglycerides and exacerbate liver fibrosis (161).…”

“…For instance, on one hand, monocyte-derived liver TRMs appear to less efficiently promote storage of triglycerides and exacerbate liver fibrosis (161). On the other hand, mice lacking CCR2, which prevented monocytederived liver TRM seeding, resulted in increased liver fibrosis (162). These seemingly contradictory results may actually represent functional evolution of monocyte-derived liver TRMs, ultimately supporting the notion that the time spent in a particular tissue, particularly as the nature of that tissue changes, informs the function and metabolic state of the TRM.…”