P2X7R: pivotal player in sepsis-induced liver damage

Sepsis results from a systemic inflammatory response to infection and, despite significant advances in medical assistance, it remains a leading cause of death in non-cardiac intensive care units worldwide [1]. Clinical evidence suggests that hepatic protection is critical for host survival, as the liver is the main organ involved in the development and perpetuation of systemic inflammation [2]. A hallmark of the inflammatory condition is increased concentration of extracellular nucleotides, notably ATP, which boosts inflammation via purinergic receptors [3]. The study by Larrouyet-Sarto et al. [4], in this issue, investigated the role of the ATP-gated P2X7 receptor (P2X7R) in sepsis-induced inflammation, oxidative damage, and liver injury.

Sepsis was induced in wildtype (WT) and P2X7 receptor-deficient (P2X7^−/−) C57BL/6 mice by cecal ligation and puncture (CLP). Sham-operated animals were used as controls. Hepatic injury was confirmed by measurement of aspartate aminotransferase (AST) and alanine transaminase (ALT) levels in the plasma. Oxidative stress in the liver tissue was linked to total sulfhydryl content, thiobarbituric acid-reactive substances, and nitric oxide (NO) levels. Superoxide dismutase (SOD) activity and 2′,7′-Dichlorofluorescein oxidation capacity in liver homogenates were also measured.

Increased P2X7R expression was detected in the liver of WT septic mice as compared with the relative sham controls. AST and ALT levels were higher in WT than in P2X7-deficient septic mice, supporting the role of P2X7R in sepsis-associated liver injury. In accordance with previous studies, increased production of reactive oxygen species, lipid peroxidation, and nitrite content were found in the liver of WT septic mice [5]. Such changes were milder in P2X7-deficient animals, confirming a P2X7R-dependent generation of reactive oxygen and nitrogen species by murine myeloid cells [6, 7]. Larrouyet-Sarto et al. also observed sepsis-induced increased levels of NADPH oxidase 1 and 2 in the liver of WT septic mice, but not in P2X7^−/− animals, suggesting a role for P2X7R in the disease pathogenesis by promoting oxidative responses in the liver. This observation is in accordance with previous reports showing P2X7R-dependent oxidative stress, inflammation, and fibrosis associated to nonalcoholic steatohepatitis [8]. Accordingly, P2X7R antagonism by Brilliant Blue G prevents acetaminophen hepatotoxicity by reducing tissue oxidative stress [9].

In septic patients, the antioxidant capacity is directly correlated with the severity of the disease and clinical outcome. Catalase (CAT) and SOD are important antioxidant hepatic enzymes that have a protective role in several pathological conditions [10]. Larrouyet-Sarto et al. provided evidence for involvement of P2X7R in alteration of the CAT-mediated antioxidant response in the liver. Septic WT mice presented lower CAT activity as compared with the relative sham control group. No differences were observed in SOD activity, although the ratio between SOD/CAT enzymatic activities was suggestive of H₂O₂ accumulation in septic WT animals. This alteration was not present in P2X7^−/− septic animals, confirming the disruptive role of this receptor on antioxidant responses. P2X7^−/− septic mice had significantly lower hepatic levels of the pro-inflammatory cytokines IL-1β and TNF-α, that have been previously shown to promote NO synthase2 (NOS2) expression in the liver [11]. Accordingly, the same animals presented reduced levels of NOS2, nitrite, and immune cell infiltration in the liver.

Larrouyet-Sarto’s study provides evidence for a role of P2X7R in promoting liver inflammation and sepsis-mediated tissue damage, supporting the idea of P2X7R-targeting therapies. However, to further confirm the authors’ findings, the effect of pharmacological inhibition of P2X7R in similar experimental models (e.g., sepsis induction by cecal ligation and puncture in WT mice) should be assessed. In fact, in other experimental settings, genetic deletion of the receptor led to a different outcome than pharmacological inhibition, suggesting caution in extending findings obtained in P2X7 null mice to the therapeutic application of P2X7 targeting compounds [12]. This would also provide information on the role of the receptor in the hepatic steatosis observed in P2X7^−/− mice and attributed to disrupted glucose metabolism as consequence of P2X7 genetic deletion. Another interesting development of the study would be the evaluation of administration of soluble ectonucleotidases, a condition that has shown beneficial effects in other inflammatory conditions [13].

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Conflict of interest

Marta Vuerich declares that he/she has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.