Liver Macrophages: Old Dogmas and New Insights

Abstract

Inflammation is a hallmark of virtually all liver diseases, such as liver cancer, fibrosis, nonalcoholic steatohepatitis, alcoholic liver disease, and cholangiopathies. Liver macrophages have been thoroughly studied in human disease and mouse models, unravelling that the hepatic mononuclear phagocyte system is more versatile and complex than previously believed. Liver macrophages mainly consist of liver-resident phagocytes, or Kupffer cells (KCs), and bone marrow-derived recruited monocytes. Although both cell populations in the liver demonstrate principal functions of macrophages, such as phagocytosis, danger signal recognition, cytokine release, antigen processing, and the ability to orchestrate immune responses, KCs and recruited monocytes retain characteristic ontogeny markers and remain remarkably distinct on several functional aspects. While KCs dominate the hepatic macrophage pool in homeostasis ("sentinel function"), monocyte-derived macrophages prevail in acute or chronic injury ("emergency response team"), making them an interesting target for novel therapeutic approaches in liver disease. In addition, recent data acquired by unbiased large-scale techniques, such as single-cell RNA sequencing, unraveled a previously unrecognized complexity of human and murine macrophage polarization abilities, far beyond the old dogma of inflammatory (M1) and anti-inflammatory (M2) macrophages. Despite tremendous progress, numerous challenges remain in deciphering the full spectrum of macrophage activation and its implication in either promoting liver disease progression or repairing injured liver tissue. Being aware of such heterogeneity in cell origin and function is of crucial importance when studying liver diseases, developing novel therapeutic interventions, defining macrophage-based prognostic biomarkers, or designing clinical trials. Growing knowledge in gene expression modulation and emerging technologies in drug delivery may soon allow shaping macrophage populations toward orchestrating beneficial rather than detrimental inflammatory responses.

Figure 1

Old dogmas versus new insights on liver macrophages. Liver macrophages have long been regarded as a homogeneous population and designated as F4/80⁺ KCs. Innovative new techniques, such as cell tracking, multi‐omics phenotyping, and single‐cell RNA sequencing, unraveled a previously unrecognized heterogeneity in liver macrophage origins and functions. The simplistic dichotomic view of M1‐ versus M2‐polarized macrophages also appears outdated as macrophages of virtually all intermediate phenotypes have been described depending on the pathology or activating signals they are exposed to. Considering the multifaceted roles of liver macrophages in promoting or preventing tissue damage and repair, immunomodulating (e.g., gene expression modulation, chemokine receptor antagonism, à la carte activating signals) rather than immunodepleting approaches need to be considered.