How TAM receptors on monocytes and macrophages regulate the immune system in liver cirrhosis

Infectious complications substantially contribute to the high morbidity and mortality in patients with cirrhosis. Increased susceptibility to infection has been attributed to immuneparesis and monocyte dysfunction. The underlying immune-pathophysiology and the onset of immuneparesis during cirrhosis progression remain elusive. TAM receptors (Tyro-3, AXL, MERTK), expressed predominantly on monocytes and macrophages, are important regulators of innate immune responses to microbial challenge and promote phagocytosis of apoptotic cells named efferocytosis. Monocytic-myeloid-derived suppressor cells (M-MDSCs) have been defined as CD14+CD15-CD11b+HLA-DR-, inhibit T cell activation and dampen immune responses in inflammatory conditions.
We sought to evaluate differential TAM receptor expression on circulatory monocytes in patients with cirrhosis in relation to monocyte function and disease severity. In addition, we investigated the function and derivation of M-MDSCs in the circulation of patients with compensated and decompensated cirrhosis. In sum, we aimed to understand how distinct monocytic subsets alter innate immune functions in patients at different stages of cirrhosis and to identify potential immunotherapeutic targets.
For this, blood specimens, peripheral blood mononuclear cells, and clinical parameters were collected from patients with cirrhosis and compared to healthy subjects. Phenotypic and functional characterisation of monocytes and M-MDSCs was assessed ex vivo using diverse techniques including flow cytometry. Models to generate and modulate different monocytic subsets were developed in vitro.
We observed an expansion of both AXL-expressing monocytes and M-MDSCs in patients with cirrhosis, increasing with disease severity. Both subsets were almost absent in healthy subjects. Numbers of M-MDSCs were increased in compensated as well as decompensated cirrhosis and substantially elevated in acutely decompensated cirrhosis and acute-on-chronic liver failure. AXL-expressing monocytes similarly expanded from early to advanced cirrhosis but were almost not present upon acute decompensation. AXL-expressing monocytes characterised as CD14+HLA-DR+CD16+ cells were phenotypically different from M-MDSCs (CD14+CD15-CD11b+HLA-DR-AXLlow/neg). Functionally, these two subsets shared certain immune-suppressive properties manifested as impaired secretion of pro-inflammatory cytokines in response to lipopolysaccharide, and impairment of T cell proliferation. However, in contrast to M-MDSCs, which displayed impaired bacterial uptake, AXL-expressing monocytes showed enhanced pathogen uptake and efferocytosis. Whereas both, AXL-expressing monocytes and M-MDSCs could be generated upon exposure to specific toll-like receptor ligands and inflammatory factors in vitro, AXL up-regulation on monocytes followed also pathogen and apoptotic cell uptake. The expansion of both subsets strongly correlated with disease severity scores and indicated infection susceptibility, morbidity and mortality. Immune responses were restored by AXL inhibition and down-regulation reversing TNF-α responses and administration of poly(I:C) reducing proportions of M-MDSCs.
We hereby characterised two distinct immune-regulatory monocytic subsets which evolved with disease severity and substantially contributed to immuneparesis and may in turn explain the high susceptibility to infection and poor clinical outcome in patients with cirrhosis. Clinical associations underline their potential value as prognostic markers. Immunotherapeutic modulation of AXL-expressing monocytes and M-MDSCs may represent options which deserve future evaluation to augment immune responses and reduce infection susceptibility, morbidity and mortality in cirrhosis.