The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis

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Abstract

SUMMARY Sepsis and septic shock are associated with life-threatening organ dysfunction caused by an impaired host response to infections. Although circadian clock disturbance impairs the early inflammatory response, its impact on post-septic immunosuppression remains poorly elucidated. Here, we show that Bmal1, a core circadian clock gene, plays a role in the regulation of host immune responses in experimental sepsis. Mechanistically, Bmal1 deficiency in macrophages increases PKM2 expression and lactate production, which is required for expression of the immune checkpoint protein PD-L1 in a STAT1-dependent manner. Consequently, targeted ablation of Pkm2 in myeloid cells or administration of anti-PD-L1-neutralizing antibody or supplementation with recombinant interleukin-7 (IL-7) facilitates microbial clearance, inhibits T cell apoptosis, reduces multiple organ dysfunction, and reduces septic death in Bmal1-deficient mice. Collectively, these findings suggest that the circadian clock controls the immune checkpoint pathway in macrophages and therefore represents a potential therapeutic target for lethal infection.

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H. Wang, O Bloom, M. Zhang … (1999)

Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.

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Gustavo Matute-Bello, Gregory Downey, Bethany B. Moore … (2011)

Acute lung injury (ALI) is well defined in humans, but there is no agreement as to the main features of acute lung injury in animal models. A Committee was organized to determine the main features that characterize ALI in animal models and to identify the most relevant methods to assess these features. We used a Delphi approach in which a series of questionnaires were distributed to a panel of experts in experimental lung injury. The Committee concluded that the main features of experimental ALI include histological evidence of tissue injury, alteration of the alveolar capillary barrier, presence of an inflammatory response, and evidence of physiological dysfunction; they recommended that, to determine if ALI has occurred, at least three of these four main features of ALI should be present. The Committee also identified key "very relevant" and "somewhat relevant" measurements for each of the main features of ALI and recommended the use of least one "very relevant" measurement and preferably one or two additional separate measurements to determine if a main feature of ALI is present. Finally, the Committee emphasized that not all of the measurements listed can or should be performed in every study, and that measurements not included in the list are by no means "irrelevant." Our list of features and measurements of ALI is intended as a guide for investigators, and ultimately investigators should choose the particular measurements that best suit the experimental questions being addressed as well as take into consideration any unique aspects of the experimental design.

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Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages.

Eva M. Pålsson-McDermott, Anne M Curtis, Gautam Goel … (2015)

Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. We show that LPS-induced PKM2 enters into a complex with Hif-1α, which can directly bind to the IL-1β promoter, an event that is inhibited by activation of PKM2. Both compounds inhibited LPS-induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1β production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.