Asia Pac Allergy.  2014 Oct;4(4):187-196. 10.5415/apallergy.2014.4.4.187.

Role of inflammasome activation in development and exacerbation of asthma

• Lee TH
• Song HJ
• Park CS

• KMID: 2397099
• DOI: http://doi.org/10.5415/apallergy.2014.4.4.187

Abstract

Human airways contact with pathogen-associated molecular patterns and danger-associated molecular patterns present in many environments. Asthmatic's airways may be more susceptible to these patterns and lead to inflammasome activation; however, the participation of inflammasome in the development and exacerbation of asthma is not fully understood and remains controversial. Asthma is a heterogeneous group composed of different airway inflammation patterns with different underlying immune mechanisms. One mechanism is neutrophilic airway inflammation based on the axis of inflammasome activation, interleukin (IL) 1β/IL-18 production, T helper 17 activation, IL-8/IL-6 overproduction, and neutrophilic inflammation. The role of inflammasome activation has been highlighted in experimental asthma models and some evidence of inflammasome activation has been recently demonstrated in human neutrophilic asthmatic airways. In addition to caspase-1 activation, proteinase 3 and other protease from activated neutrophils directly cleave pro-IL-1β and pro-IL-18 to IL-1β and IL-18, which contribute to the phenotype of subsequent adaptive immune responses without inflammasome activation. Data suggests that neutrophilics in asthmatic airways may have an additional effect in initiating inflammasome activation and amplifying immune responses. Among the mediators from neutrophils, S100A9 seems to be one candidate mediator to explain the action of neutrophils in amplifying the airway inflammation in concert with inflammasome.

Keyword

Calgranulin B; Asthma; Inflammasomes; Neutrophils; Immunity Innate; Th17 cells

MeSH Terms

Asthma*
Calgranulin B
Humans
Inflammasomes*
Inflammation
Interleukin-18
Interleukins
Myeloblastin
Neutrophils
Pathogen-Associated Molecular Pattern Molecules
Phenotype
Th17 Cells
Calgranulin B
Inflammasomes
Interleukin-18
Interleukins
Myeloblastin
Pathogen-Associated Molecular Pattern Molecules

Figure

• 

  Fig. 1 A schematic overview of inflammasome activation. Extracellular and intracellular pathogen-associated molecular patterns (PAMPs) are recognized by Toll-like receptors (TLRs), which results in the transcription of pro-IL-1β and pro-IL-18 cytokines via induces nuclear factor (NF)-κB signaling. NOD-like receptor family, pyrin domain containing 3 activation (NLRP3) is induced by K+ efflux, reactive oxygen species (ROS) production, and activation of P2X7R by adenosine triphosphate (ATP). The assembly of the NLRP3 inflammasome complex, including the adaptor molecule apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) and procaspase-1, leads to caspase-1 activation. The activated caspase-1 cleaves pro-IL-1β and pro-IL-18 into their mature forms. DAMP, danger-associated molecular pattern; NOD, nucleotide-binding oligomerization domain; IL, interleukin; RIG, retinoic acidinducible gene; MDA, melanoma differentiation-associated protein; INF, interferon; TNF, tumor-necrosis factor.

• 

  Fig. 2 (A) Photographs of 2-dimensional electrophoresis protein separation of pooled sputum (n = 5) obtained from uncontrolled asthmatics with neutrophilic inflammation (>70%). Protein spots are dentified by matrix-assisted laser desorption/ionizatione time of flight/time of flight. Enlargements of spots 2 is S100 calcium binding protein A9 (S100A9). (B) Comparison of S100A9 levels in sputum between the neutrophilic (neu) and eosinophilic (eos) subtypes of severe uncontrolled asthma (UA), partially controlled asthma (PA), and controlled asthma (CA) Using enzyme-linked immunosorbent assay. Data are presented as median (interquartile range). *p < 0.01 vs. neutrophilic subtypes of severe uncontrolled asthma. Adapted from Lee TH, et al. Ann Allergy Asthma Immunol 2013;111:268-275.e1, with permission of Elsevier B. V. [62].

• 

  Fig. 3 (A) Interleukin-1β enhances S100 calcium binding protein A9 protein expression in cell extracts of THP-1 monocyte stimulated for 24 hours to 96 hours in the presence of CaCl2. (B) S100A9 dose - dependently induces inflammasome activation by cleaving procaspase-1 into P20 activated caspase-1 in the monocyte cell lines.

• 

  Fig. 4 Interaction of inflammasome activation and S100A9 in neutrophilic inflammation of asthma. Asthma is characterized by the airway infiltration of eosinophils and mast cells. IgE-dependent asthma is under the influence of the T helper 2 (Th2)-cytokines (interleukin [IL] 4, IL-5, and IL-13) generated by Th2-type cells. In T-cell independent manner, TSLP and IL-33 released from the activated epithelium stimulates mast cells to release the Th2-type effector cytokines. These can attract and activate eosinophils and mast cells. As another pathway, PAMPs and DAMPs including offending allergens induces nuclear factor (NF)-κB activation via Toll-like receptor (TLR) and concurrent inflammasome activation via nucleotide-binding oligomerization domain (NOD) receptors; subsequent activation of Th17 cells to regulate both neutrophilic and macrophage inflammation. TSLP, thymic stromal lymphopoietin, pathogen-associated molecular patterns; NLRP3, NOD-like receptor family, pyrin domain containing 3 activation; PAMP, damage-associated molecular patterns; DAMP, danger-associated molecular pattern; INF, interferon; TNF, tumor-necrosis factor.

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