The double sides of NLRP3 inflammasome activation in sepsis

Abstract

Sepsis is defined as a life-threatening organ dysfunction induced by a dysregulated host immune response to infection. Immune response induced by sepsis is complex and dynamic. It is schematically described as an early dysregulated systemic inflammatory response leading to organ failures and early deaths, followed by the development of persistent immune alterations affecting both the innate and adaptive immune responses associated with increased risk of secondary infections, viral reactivations, and late mortality. In this review, we will focus on the role of NACHT, leucin-rich repeat and pyrin-containing protein 3 (NLRP3) inflammasome in the pathophysiology of sepsis. NLRP3 inflammasome is a multiproteic intracellular complex activated by infectious pathogens through a two-step process resulting in the release of the pro-inflammatory cytokines IL-1β and IL-18 and the formation of membrane pores by gasdermin D, inducing a pro-inflammatory form of cell death called pyroptosis. The role of NLRP3 inflammasome in the pathophysiology of sepsis can be ambivalent. Indeed, although it might protect against sepsis when moderately activated after initial infection, excessive NLRP3 inflammasome activation can induce dysregulated inflammation leading to multiple organ failure and death during the acute phase of the disease. Moreover, this activation might become exhausted and contribute to post-septic immunosuppression, driving impaired functions of innate and adaptive immune cells. Targeting the NLRP3 inflammasome could thus be an attractive option in sepsis either through IL-1β and IL-18 antagonists or through inhibition of NLRP3 inflammasome pathway downstream components. Available treatments and results of first clinical trials will be discussed.

Modulation of Autophagy and Cell Death by Bacterial Outer-Membrane Vesicles

“…We showed that this overactivation was caused by OMV-associated autophagic blockade and the loss of negative feedback control [ 68 ]. This situation is deleterious for the host since the uncontrolled inflammatory burst is not efficient at fighting against infection and can progress to sepsis and threaten patients’ lives in severe cases [ 72 , 75 ]. OMVs could be key players in the establishment of sepsis due to their nanostructure allowing their dissemination and their pro-inflammatory properties.…”

Amyloid-β and caspase-1 are indicators of sepsis and organ injury

“…Similar to previous studies [19][20][21], our ICU-sepsis group displayed significantly increased IL-18, IL-1β (figures 1a and b), IL-6, CXCL-8, IL-10, and MCP-1 compared to either or both of the ICU-non-sepsis patient and healthy cohorts (supplemental figure 1). During infection and sepsis, the NLRP3-inflammasome initiates pro-caspase-1 activation via auto-proteolysis [22][23][24]. Active caspase-1 is a pro-inflammatory cysteine active site aspartate-specific protease that cleaves pro-IL-1β and pro-IL-18 into their active forms (reviewed in [25]).…”

Linoleic acid‐derived diol 12,13‐DiHOME enhances NLRP3 inflammasome activation in macrophages

“…N‐GSDMD pores mediate selective IL‐1β secretion and eventually a programmed lytic cell death pathway called pyroptosis, thus releasing more inflammatory DAMPs into the extracellular milieu 2 . Although the NLRP3 inflammasome is important for the physiological host immune response, its dysregulated activation contributes to hyper‐inflammation and tissue injury in diseases like sepsis 4 . Identifying the factors that influence NLRP3 inflammasome priming and activation will improve our mechanistic understanding and treatment of inflammatory diseases.…”

“…2 Although the NLRP3 inflammasome is important for the physiological host immune response, its dysregulated activation contributes to hyper-inflammation and tissue injury in diseases like sepsis. 4 Identifying the factors that influence NLRP3 inflammasome priming and activation will improve our mechanistic understanding and treatment of inflammatory diseases.…”