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The liver macrophage population comprises resident Kupffer cells (KCs) and monocyte-derived macrophages with distinct pro- or anti-inflammatory properties that affect the severity and course of liver diseases. The mechanisms underlying macrophage differentiation and functions in metabolic dysfunction-associated steatotic liver disease and/or steatohepatitis (MASLD/MASH) remain mostly unknown. Using single-cell RNA sequencing (scRNA-seq) and fate mapping of hepatic macrophage subpopulations, we unraveled the temporal and spatial dynamics of distinct monocyte and monocyte-derived macrophage subsets in MASH. We revealed a crucial role for the Notch-Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) signaling pathway in controlling the monocyte-to-macrophage transition, with Rbpj deficiency blunting inflammatory macrophages and monocyte-derived KC differentiation and conversely promoting the emergence of protective Ly6C lo monocytes. Mechanistically, Rbpj deficiency promoted lipid uptake driven by elevated CD36 expression in Ly6C lo monocytes, enhancing their protective interactions with endothelial cells. Our findings uncover the crucial role of Notch-RBPJ signaling in monocyte-to-macrophage transition and will aid in the design of therapeutic strategies for MASH treatment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Myeloid cells, including monocytes, macrophages, dendritic cells, and polymorphonuclear cells are key components of homeostasis maintenance and immune response. Among the myeloid lineage, macrophages stand out as highly versatile cells that safeguard tissue functions but also sense and respond to potentially harmful microenvironmental cues. Numerous studies have demonstrated that the nutritional status and macronutrient availability affect macrophage identity and function. However, the exact mechanistic links between macronutrient intake and cellular metabolic shifts are only beginning to be understood. In this chapter, we explore how dietary "macros"-carbohydrates, fats, and amino acids-impact the immunomodulatory activity of macrophages in healthy and inflamed tissues., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Resident tissue macrophages (RTMs) have a broad spectrum of immune- and non-immune-related tissue-supporting activities. The roots of this heterogeneity and versatility are only beginning to be understood. Here, we propose a conceptual framework for considering the RTM heterogeneity that organizes the factors shaping RTM identity within four cardinal points: (1) ontogeny and the view that adult RTM populations comprise a defined mixture of cells that arise from either embryonic precursors or adult monocytes; (2) local factors unique to the niche of residence, evolving during development and aging; (3) inflammation status; and (4) the cumulative effect of time spent in a specific tissue that contributes to the resilient adaptation of macrophages to their dynamic environment. We review recent findings within this context and discuss the technological advances that are revolutionizing the study of macrophage biology., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Resident tissue macrophages (RTMs) are cells with a high functional plasticity assuming pleiotropic roles in their tissue of residence, from clearance of dead cells and metabolic sensing in steady state to cytokine production and tissue repair during inflammation. The liver has long been considered as only populated by Kupffer cells (KCs), a macrophage population assumed to be in charge of all of these functions. However, we know now that KCs are not the only macrophage population in the liver, that recently was shown to contain also capsular macrophages, monocyte-derived macrophages as well as recruited peritoneal macrophages inherited from previous inflammatory events. These macrophages exhibit different origins, time of establishing residence and locations in the liver, with both ontogenical and environmental factors shaping their identity and functions. Furthermore, liver macrophages reside in a complex environment with a pronounced metabolic zonation. Here, we briefly discuss how these intrinsic and extrinsic factors influence macrophage biology and liver physiology in general. We notably focus on how the recent advances of single cell transcriptomic approaches are changing our understanding of liver macrophages and diseases., (Copyright © 2019 Blériot and Ginhoux.)

In this issue of Cell, Uderhardt et al. employed intravital two-photon microscopy to examine tissue-resident macrophage responses to sterile cellular injuries of variable size. They observed that while multi-cell "macrolesions" are characteristically pro-inflammatory, resident macrophages can "cloak" single-cell microlesions to prevent excessive neutrophil recruitment and limit subsequent tissue damage., (Copyright © 2019 Elsevier Inc. All rights reserved.)