Regulation of Monocyte-Macrophage Responses in Cirrhosis—Role of Innate Immune Programming and Checkpoint Receptors

Abstract

Many aspects of the innate immune system have been studied in cirrhosis, and abnormalities have been described supporting both a pro-inflammatory and anti-inflammatory phenotype of myeloid cells. However, the findings of these studies vary by stage of disease and methodology. The recent description of the syndrome of acute-on-chronic liver failure (ACLF) has refined our understanding of the natural history of cirrhosis. In this context, we review the regulatory mechanisms at play that contribute to the immune abnormalities described in advanced liver disease. Specifically, we review the evidence for epigenetic mechanisms regulating monocyte phenotype, and the role of checkpoint receptors on regulating innate and adaptive immune cell function.

Altered bioenergetics and mitochondrial dysfunction of monocytes in patients with COVID‐19 pneumonia

“…TIM‐3 is expressed on monocytes in different clinical and pathological settings, and it can synergize with Toll‐like receptors (Anderson et al , 2007; Riva & Mehta, 2019). The precise role of TIM‐3 in monocyte biology is controversial and still scarcely understood.…”

“…The precise role of TIM‐3 in monocyte biology is controversial and still scarcely understood. However, in general, expression of inhibitory immune checkpoints, like PD‐1, PD‐L1, and TIM‐3, has been linked to a more suppressive phenotype and worse prognosis in sepsis, infections, and even cancer (Zasada et al , 2017; Wang et al , 2017; Tai et al , 2018; Riva & Mehta, 2019). We found that in COVID‐19 patients, a higher percentage of PD‐1 + and PD‐L1 + cells were present among total monocytes, as well as within different subsets (Fig 2E, and Appendix Fig A and B).…”

“…Monocyte subsets differ for their ability to present antigens and produce pro‐inflammatory cytokines, as well as to express specific homing receptors. Interestingly, they can upregulate the so‐called inhibitory receptors belonging to the family of immune checkpoints, such as PD‐1 and its ligands (including PD‐L1), in several pathological conditions (Zasada et al , 2017; Wang et al , 2017; Tai et al , 2018; Riva & Mehta, 2019).…”

Macrophages in Chronic Liver Failure: Diversity, Plasticity and Therapeutic Targeting

“…Immune checkpoints constitute a complex array of receptors (e.g., PD-1, CTLA-4) and their ligands (e.g., PD-L1/PD-L2, CD80/ C86) expressed on both innate and adaptive immune cells, which exert key regulatory roles during homeostasis and inflammatory pathologies, mainly in chronic infection, sepsis and cancer. Immune checkpoint inhibition has become an emerging therapeutic strategy in various liver diseases (203,213). For instance, we have demonstrated that peripheral CD4+ T cells from ALF patients have increased CTLA-4 expression and reduced proliferative response to stimulation that can be enhanced via CTLA-4 inhibition in vitro (214).…”

“…The concept of "innate immune memory" has arisen over recent years which may open another window of opportunity for new therapies in chronic liver diseases (203). This idea stems from studies demonstrating that epigenetic mechanisms regulate macrophage function by imprinting them with a "memory response" towards future stimuli.…”