The NLRP3 inflammasome as a new target in respiratory disorders treatment

Abstract

In recent years a continuous increase in new cases of respiratory disorders, such as rhinitis, asthma, and chronic obstructive pulmonary disease (COPD), has been observed. The exact pathomechanism of these diseases is still blurry, resulting in the lack of targeted and effective therapy. The conventional use of treatment strategies, such as antihistamine drugs and/or glucocorticosteroids act mainly symptomatically and have significant side effects. Specific allergen immunotherapy is only useful in the management of specific allergies and selected patients. Therefore, new therapeutic solutions are constantly being sought. The novelty of recent years has been the association between NLRP3 inflammasome activation and the development of airway inflammatory diseases. This seems to be an interesting therapeutic target that may support or even replace traditional therapies in the future. The review presented, discusses the contribution of NLRP3 inflammasome to the development of allergic rhinitis, allergic asthma, and COPD. Moreover, the modulatory properties of probiotics as potential inhibitors of NLRP3 inflammasome are emphasised.

Keywords: IL-1β; NLRP3 inflammasome; allergic asthma; allergic rhinitis; anti-inflammatory; chronic obstructive pulmonary disease; probiotics; treatment.

Figure 1

Structure of the NLRP3 inflammasome. NLRP3 inflammasome consists of NLRP3 contains the N-terminal pyrin domain (PYD), central NACHT domain (nucleotide-binding oligomerization domain) and C-terminal leucine-rich repeat domain (LRRs); ASC, which is composed of PYD and CARD (cysteinyl aspartate-specific proteinase (caspase) recruitment domain) through which it interacts with NLRP3 and Caspase-1 respectively; Caspase-1 which is composed of 10- and 20-kDa subunits.

Figure 2

Activation of the NLRP3 inflammasome. Microbial components and endogenous cytokines provide the priming signal (signal 1) which activates the transcription factor NF-κB and leads to overexpression of NLRP3, pro-IL-1β, and pro-IL-18. Activation signal (signal 2) is provided by bacterial and fungal components and toxins, pathogen-associated RNA, ATP, K+ efflux, reactive oxygen species (ROS), or lysosomal damage, and leads to the activation of NLRP3 inflammasome and release of active Caspase-1. Caspase-1 cleaves the pro-IL-1β, pro-IL-18 and GSDMD to their mature forms, which are then secreted extracellularly. NLRP3, NOD-like receptor family pyrin domain containing 3; ATP, adenosine triphosphate; PAMP, pathogen-associated molecular pattern; ROS, reactive oxygen species; IL, interleukin; LPS, lipopolysaccharide; GSDMD, gasdermin D.

Figure 3

Proposed mechanism of probiotic actions on the NLRP3 inflammasome activation pathway. Inhibition of the NLRP3 inflammasome by probiotic bacteria could occur by inhibiting TLRs and NODs receptors, lowering their expression, downregulating NF-κB expression or inhibiting its movement to the nucleus. Probiotics may work by inhibiting inflammasome formation and Caspase-1 activation, which leads to a decrease in the level of IL-1β and IL-18 release. Potential inhibition of ROS production by probiotic bacteria would lead to a reduction in NLRP3 inflammasome activation.