Blocking Enzyme May Fix Immune Dysfunction in ACLF

A Belgian study has opened up a potential new treatment option for reversing monocyte dysfunction in acute-on-chronic liver failure (ACLF).

“Metabolic rewiring of the cells using a pharmacological inhibitor of glutamine synthetase partially restored the phagocytic and inflammatory capacity of in vitro generated- as well as ACLF patient-derived monocytes,” wrote Hannelie Korf, PhD, of the Catholic University of Leuven, Belgium, and colleagues in the journal Gut.

They noted that in ACLF, monocytes exhibit a distinct transcriptional profile that polarizes these cells toward an immunotolerant state and altered metabolism. ACLF patients are highly susceptible to infections, and monocytes are the first line of defence against pathogens entering the circulation. Failed monocytic response to danger signals may be due to an overproduction of immunosuppressive factors and/or the induction of a tolerant state, the investigators noted. Bacterial infection in ACLF frequently precipitates multi-organ failure.

The researchers recruited healthy controls, patients with decompensated alcoholic cirrhosis, and patients with ACLF who were diagnosed at the University Hospital of Leuven from July 2013 to May 2017.

In various tests, monocytes from the ACLF group showed a broad range of innate immune defects beyond those previously documented, the authors noted. “This monocyte immunosuppressive signature in ACLF is clearly different from decompensated cirrhosis supporting ACLF as a distinct clinical entity,” they wrote.

For example, ACLF monocytes featured such defects as elevated levels of precursors of the anti-inflammatory cytokine interleukin 10 (IL-10), as well as reduced human leukocyte antigen DR isotype expression, and impaired phagocytic and oxidative burst capacity. The ACLF cells also showed upregulation of other immunosuppressive parameters and compromised antibacterial and antigen-presentation machinery.

In contrast, monocytes from decompensated cirrhosis patients showed an intact ability to respond to inflammatory triggers. And when healthy monocytes were cultured in ACLF plasma, they mimicked the immunosuppressive characteristics observed in patients, including a blunted phagocytic response and metabolic program associated with an immune-tolerant state.

The researchers fed glutamine into the tricarboxylic acid cycle using methionine sulfoximine (MSO), a pharmacologic inhibitor of glutamine synthetase (GLUL). This enzyme is involved in controlling the release of inflammatory mediators and cellular autophagy. This process partially restored the phagocytic and inflammatory capacity of both patient-derived and lab-generated monocytes. In addition to improving the bacteria-engulfing capacity of monocytes, MSO also inhibited IL-10 production and promoted production of the proinflammatory cytokine tumor necrosis factor.

And the findings had a clinical correlation. “Underscoring the biological relevance of this finding, we detected a positive correlation between GLUL/glutaminase ratio and the model for end-stage liver disease (MELD),” Korf’s group wrote.

“The results from this study are very exciting,” Vinay Sundaram, MD, of Cedars-Sinai Medical Center in Los Angeles, told MedPage Today, offering his perspective as someone not involved in the research. He noted that the findings shed additional light on the physiologic differences between ACLF and acute hepatic decompensation by identifying the mechanisms by which monocytes become immunotolerant in ACLF.

“Furthermore, the tricarboxylic acid cycle has been identified as a unique target to reverse monocyte dysfunction,” Sundaram continued. “I envision that this pathway can be targeted for emerging therapies in both ACLF and severe alcoholic hepatitis.”

He added that phase I clinical trials are in order.

Interestingly, similar immunosuppressive features and metabolic/epigenetic reprogramming have been observed in monocytes from patients with late-stage sepsis. And in cancer research, a similar metabolic rewiring of tumor-associated macrophages through GLUL inhibition promoted immunostimulatory and antiangiogenic effects that prevented the development of metastasis.

The authors concluded that metabolic programs can be manipulated to rescue defective monocyte phagocytic functions. “This work highlights the importance of metabolic immunotherapeutic strategies in the treatment of ACLF, and it will be intriguing for future work to further fine tune and develop this approach as a potential interventional strategy,” they wrote.