IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis

Abstract

Dysregulated inflammasome activation contributes to respiratory infections and pathologic airway inflammation. Through basic and translational approaches involving murine models and human genetic epidemiology, we show here the importance of the different inflammasomes in regulating inflammatory responses in mice and humans with cystic fibrosis (CF), a life-threatening disorder of the lungs and digestive system. While both contributing to pathogen clearance, NLRP3 more than NLRC4 contributes to deleterious inflammatory responses in CF and correlates with defective NLRC4-dependent IL-1Ra production. Disease susceptibility in mice and microbial colonization in humans occurrs in conditions of genetic deficiency of NLRC4 or IL-1Ra and can be rescued by administration of the recombinant IL-1Ra, anakinra. These results indicate that pathogenic NLRP3 activity in CF could be negatively regulated by IL-1Ra and provide a proof-of-concept evidence that inflammasomes are potential targets to limit the pathological consequences of microbial colonization in CF.

<b><i>Pseudomonas aeruginosa</i></b> and <b><i>Klebsiella</i></b> <b><i>pneumoniae</i></b> Adaptation to Innate Immune Clearance Mechanisms in the Lung

“…However, several studies fail to demonstrate that inflammasome activation promotes P. aeruginosa clearance [39, 40, 45]. Mice lacking inflammasome components, or those that had been treated with anakinra, which blocks IL-1 signaling, in fact had significantly increased ability to clear P. aeruginosa [39]. These studies do not support the hypothesis that decreased expression of PAMPs is a bacterial mechanism to increase survival within the lung by limiting inflammation.…”

“…This diminished expression of PAMPs is usually interpreted as bacterial strategy to avoid the activation of the inflammasome and resulting production of IL-1β and recruitment of phagocytes [28, 44]. However, several studies fail to demonstrate that inflammasome activation promotes P. aeruginosa clearance [39, 40, 45]. Mice lacking inflammasome components, or those that had been treated with anakinra, which blocks IL-1 signaling, in fact had significantly increased ability to clear P. aeruginosa [39].…”

“…Flagellin can also activate surface TLR5 receptors to induce NF-κB-dependent inflammation [41]. LPS, which is recognized by the TLR4/MD2 surface complex, triggers NLRP3/ASC-dependent inflammasome activation and cleavage of caspase-1, which processes pro-IL-1β into mature IL-1β [38, 39]. Surface TLR4/MD2 engagement also primes NF-κB signaling [42].…”

Innate Lung Defense during Invasive Aspergillosis: New Mechanisms

“…It demonstrated that melanin found in the A. fumigatus cell wall, while potently inducing proinflammatory cytokine production, failed to induce ROS production in human monocytes as a result of specific inhibition of the interaction between the p22phox subunit of flavocytochrome b558 with the NADPH oxidase complex. Importantly, in the aforementioned reports detailing the IA inflammation affiliated with CGD and CF, employing IL-1R blockade restored LC3 phagolysosome formation in the monocytes from CGD patients [49] as well as in the macrophages from mice deficient in CFTR [50] .…”

“…Excessive inflammation observed during IA in chronic granulomatous disease (CGD) is IL-1-dependent and can be ameliorated by IL-1R blockade [49] . Similarly, studies have shown that NLRP3 inflammasome-mediated responses during A. fumigatus exposure in murine and human cystic fibrosis (CF) is a result of defective IL-1RA production, which can be minimized by treating with anakinra (recombinant IL-1RA) [50] . Collectively, while IL-1R signaling is essential for the elimination of A. fumigatus from the lungs, in specific inflammatory conditions such as CGD and CF, IL-1R signaling rather serves as a therapeutic target for inhibition.…”