Bioenergetic Failure Drives Functional Exhaustion of Monocytes in Acute-on-Chronic Liver Failure

Deepanshu Maheshwari, Dhananjay Kumar, Rakesh Kumar Jagdish, Nidhi Nautiyal, Ashinikumar Hidam, Rekha Kumari, Rashi Sehgal, Nirupama Trehanpati, Sukriti Baweja, Guresh Kumar, Swati Sinha, Meenu Bajpai, Viniyendra Pamecha, Chhagan Bihari, Rakhi Maiwall, Shiv Kumar Sarin, Anupam Kumar, Deepanshu Maheshwari, Dhananjay Kumar, Rakesh Kumar Jagdish, Nidhi Nautiyal, Ashinikumar Hidam, Rekha Kumari, Rashi Sehgal, Nirupama Trehanpati, Sukriti Baweja, Guresh Kumar, Swati Sinha, Meenu Bajpai, Viniyendra Pamecha, Chhagan Bihari, Rakhi Maiwall, Shiv Kumar Sarin, Anupam Kumar

Abstract

Objective: The monocyte-macrophage system is central to the host's innate immune defense and in resolving injury. It is reported to be dysfunctional in acute-on-chronic liver failure (ACLF). The disease-associated alterations in ACLF monocytes are not fully understood. We investigated the mechanism of monocytes' functional exhaustion and the role of umbilical cord mesenchymal stem cells (ucMSCs) in re-energizing monocytes in ACLF.

Design: Monocytes were isolated from the peripheral blood of ACLF patients (n = 34) and matched healthy controls (n = 7) and patients with compensated cirrhosis (n = 7); phagocytic function, oxidative burst, and bioenergetics were analyzed. In the ACLF mouse model, ucMSCs were infused intravenously, and animals were sacrificed at 24 h and day 11 to assess changes in monocyte function, liver injury, and regeneration.

Results: Patients with ACLF (alcohol 64%) compared with healthy controls and those with compensated cirrhosis had an increased number of peripheral blood monocytes (p < 0.0001) which displayed significant defects in phagocytic (p < 0.0001) and oxidative burst capacity (p < 0.0001). ACLF patients also showed a significant increase in the number of liver macrophages as compared with healthy controls (p < 0.001). Bioenergetic analysis showed markedly reduced oxidative phosphorylation (p < 0.0001) and glycolysis (p < 0.001) in ACLF monocytes. Patients with monocytes having maximum mitochondrial respiration of <37.9 pmol/min [AUC = 0.822, hazard ratio (HR) = 4.5] and baseline glycolysis of ≤42.7 mpH/min (AUC = 0.901, HR = 9.1) showed increased 28-day mortality (p < 0.001). Co-culturing ACLF monocytes with ucMSC showed improved mitochondrial respiration (p < 0.01) and phagocytosis (p < 0.0001). Furthermore, ucMSC therapy increased monocyte energy (p < 0.01) and phagocytosis (p < 0.001), reduced hepatic injury, and enhanced hepatocyte regeneration in ACLF animals.

Conclusion: Bioenergetic failure drives the functional exhaustion of monocytes in ACLF. ucMSCs resuscitate monocyte energy and prevent its exhaustion. Restoring monocyte function can ameliorate hepatic injury and promote liver regeneration in the animal model of ACLF.

Keywords: acute-on-chronic liver failure (ACLF); bioenergetics; monocyte; regeneration; ucMSC therapy.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Maheshwari, Kumar, Jagdish, Nautiyal, Hidam, Kumari, Sehgal, Trehanpati, Baweja, Kumar, Sinha, Bajpai, Pamecha, Bihari, Maiwall, Sarin and Kumar.

Figures

Figure 1
Figure 1
Distribution and function of peripheral blood monocytes and liver macrophages in healthy controls and acute-on-chronic liver failure (ACLF) patients. (A) Dot plot showing changes in the percentage of peripheral blood CD14+ monocytes in ACLF compared with healthy controls and those with cirrhosis. (B) Dot plot showing changes in the percentage of peripheral blood CD14+ monocytes between subgroups of ACLF (ACLF, ACLF-SIRS, and ACLF-sepsis). (C) Dot plot showing the percentage changes in phagocytosis (left) and oxidative burst (right) of peripheral blood CD14+ monocytes in ACLF compared with healthy controls and those with cirrhosis. (D) Dot plot showing the percentage changes in phagocytosis (left) and oxidative burst (right) of peripheral blood CD14+ monocytes between subgroups of ACLF (ACLF, ACLF-SIRS, and ACLF-sepsis). (E) Dot plot showing the percentage changes in the distribution of CD68+ macrophage (left) and CD14+ monocyte (right) in ACLF compared with healthy controls. (F) Dot plot showing the percentage changes in phagocytosis of CD68+ liver macrophages in ACLF compared with healthy controls (*p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001). n.s. stands for non-significant.
Figure 2
Figure 2
Energy metabolism of healthy and ACLF monocytes. (A, B) Bar graph showing changes in median fluorescence intensity of (A) phagocytosis and (B) cellular ROS of healthy CD14+ monocytes in the presence of inhibitors of mitochondria and glycolysis. (C) Real-time changes in oxygen consumption rate (OCR) with subsequent treatment with oligomycin (Oligo.) FCCP and rotenone and antimycin A (Rot. + AA.) in ACLF, cirrhosis, and healthy monocytes (left). Dot plot showing changes in basal mitochondrial respiration (middle) and glycolysis (right) in ACLF monocytes compared with healthy controls and those with cirrhosis. (D) Real-time changes in OCR and dot plot showing changes in the given mitochondrial respiratory parameter of monocytes in the ACLF subgroups (ACLF, ACLF-SIRS, and ACLF-sepsis). (E) Dot plot showing changes in glycolysis (extracellular acidification rate) of monocytes in the ACLF subgroups (ACLF, ACLF-SIRS, and ACLF-sepsis). (F) MitoTracker Green staining and (G) mitochondrial functionality based on MitoTracker Red vs. MitoTracker Green percentage in ACLF monocytes compared with healthy controls (*p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001).
Figure 3
Figure 3
Association of systemic inflammation and endotoxemia with monocyte mitochondrial respiration defects in patients with ACLF. (A) Dot plot showing changes in plasma level of pro-inflammatory and anti-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α); interleukins (IL), 6, 12, 1β, 10, 1RA, 13, and 5] in the ACLF subgroups (ACLF, ACLF-SIRS, and ACLF-sepsis). (B) Dot plot showing changes in plasma endotoxin levels in the ACLF subgroups (ACLF, ACLF-SIRS, and ACLF-sepsis). (C) Real-time changes in oxygen consumption rate (OCR) with subsequent treatment with oligomycin (Oligo.) FCCP and rotenone and antimycin A (Rot. + AA.) in healthy monocytes treated with healthy plasma (hP), ACLF plasma (aP), and ACLF plasma with LPS (aP + LPS) (*p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001). n.s. stands for non-significant.
Figure 4
Figure 4
Effect of monocyte energy metabolism on ACLF patients’ outcomes. (A) Real-time changes in oxygen consumption rate (OCR) with subsequent treatment with oligomycin (Oligo.) FCCP and rotenone and antimycin A (Rot. + AA.) (left). Dot plot showing changes in basal mitochondrial respiration (middle) and maximum mitochondrial respiration (right) of monocytes in ACLF survivors and non-survivors. (B) Dot plot showing changes in glycolysis (extracellular acidification rate) of monocytes in ACLF survivors and non-survivors. (C) Kaplan–Meyer survivorship graph showing changes in monocyte maximal respiration, basal respiration, and glycolysis (extracellular acidification rate) in ACLF survivors vs. non-survivors (*p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001).
Figure 5
Figure 5
Effect of umbilical cord mesenchymal stem cells (ucMSCs) on ACLF monocyte bioenergy and function. (A) Representative immunofluorescence confocal image of MSC donating its mitochondria to the ACLF monocyte (×60). (B) Representative histogram (left) and dot plot (right) showing mitochondrial uptake by ACLF monocytes measured through flow cytometry. (C) Representative histograms and dot plot showing changes in MitoTracker Green (total mitochondria) and MitoTracker Red (functional mitochondria) intensity in ACLF monocytes co-cultured with ucMSCs. (D) Real-time changes in oxygen consumption rate (OCR) with subsequent treatment with oligomycin (Oligo.) FCCP and rotenone and antimycin A (Rot. + AA.) in ACLF patients’ monocytes co-cultured with ucMSC, compared with control. (E) Dot plot showing changes in phagocytic activity of ACLF monocytes co-cultured with ucMSCs compared with control (*p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001).
Figure 6
Figure 6
Effect of ucMSC therapy on monocyte energy and function, liver injury, and regeneration in the animal model of ACLF. (A) Schematic diagram of MSC therapy in the ACLF animal model. (B) Dot plot showing changes in CD115+ bone marrow monocyte phagocytosis at 24 h and day 11 in control and ucMSC-treated animals. (C) Real-time changes in oxygen consumption rate (OCR) with subsequent treatment with oligomycin (Oligo.) FCCP and rotenone and antimycin A (Rot. + AA.) in CD115+ bone marrow monocytes in control and ucMSC-treated animals. (D) Representative images showing F4/80+ liver macrophages in liver tissue sections (left) and bar graphs showing changes in the number of F4/80+ cells (middle) and F4/80+ liver macrophage phagocytosis (right) in control and ucMSC-treated animals at the given time points. (E) Representative images showing hematoxylin and eosin staining of liver tissue and TUNEL+ hepatocytes (left). Dot plot showing the number of ballooned hepatocytes and TUNEL+ hepatocytes (right) in control and ucMSC-treated animals at the given time points. (F) Representative images showing PCNA+ hepatocytes in liver tissue sections (left). Bar graph showing changes in the number of PCNA+ hepatocytes (right) in control and ucMSC-treated animals at the given time points (*p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001). n.s. stands for non-significant.
Figure 7
Figure 7
Diagram showing the proposed mechanism of ucMSC therapy in ACLF. Increased systemic accumulation of DAMPS, PAMPS, and inflammatory mediators in response to acute liver injury in cirrhosis (a condition called ACLF) induces mitochondrial damage and bioenergy failure in monocytes. A broad defect in energy metabolism drives the exhaustion of phagocytic and oxidative burst function of monocytes in ACLF, required for the effective clearance of pathogens and cellular debris. This may account for the poor resolution of liver injury and infection, leading to regeneration failure, sepsis, shock, and death in ACLF. ucMSCs rejuvenate monocyte energy and function, prevent liver injury, and potentiate regeneration in ACLF animals.

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