Pathogen‐associated molecular patterns and extracellular Hsp70 interplay in NLRP3 inflammasome activation in monocytic and bronchial epithelial cellular models of COPD exacerbations

Abstract

During chronic obstructive pulmonary disease (COPD) exacerbations, interplay between pathogen‐associated molecular patterns (PAMPs; e.g. lipopolysaccharide (LPS) and lipoteichoic acid (LTA)) and damage‐associated molecular patterns (DAMPs; e.g. extracellular heat shock protein 70 (eHsp70) and adenosine triphosphate (ATP)) might influence patient’s outcome. Nucleotide‐binding oligomerization domain‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome might have a role in dysfunctional immune system in COPD. We hypothesized that LPS, LTA, eHsp70 and their combinations induce NLRP3 inflammasome activation, and we aimed to explore this assumption. We used monocytic (monocyte‐derived macrophages (MDMs) and THP‐1) and bronchial epithelial cells (NHBE and NCI‐H292) to represent systemic and local airway compartments that could be affected in COPD. Bacterial components and eHsp70 stimulated NLRP3 and interleukin (IL)‐1β gene expression as well as IL‐1β and ATP release from all cells compared to non‐treated cells. LDH secretion was induced in cell lines only. eHsp70 had inhibitory (NCI‐H292) or stimulatory (NHBE) effects on eATP levels compared to PAMP alone. Regarding NLRP3 inflammasome activation, eHsp70 had mostly antagonistic effects. We demonstrated that bacterial components and eHsp70 activate NLRP3 inflammasome and increase ATP secretion. We suggest that extracellular Hsp70 might modulate immune responses provoked by bacterial infections and affect COPD patients’ outcome during acute exacerbations.

Roles of Inflammasome in Cigarette Smoke-Related Diseases and Physiopathological Disorders: Mechanisms and Therapeutic Opportunities

“…With regard to macrophage dysfunction, the study by Buscetta et al (45) manifested that cigarette smoke restrained the expression of NLRP3, caspase-1, IL-1b, and IL-18 acting mainly at the transcriptional level in human monocyte-derived macrophages and THP-1 cells, and increased the caspase-1 activity via an NLRP3-independent and Toll-like receptor 4 (TLR4)-Toll/IL-1receptor domain containing adaptor inducing IFN-b (TRIF)-caspase-8-dependent pathway. On the contrary, Rumora et al (22,23) found that cigarette smoke was an activated factor of NLRP3 inflammasome in human monocytederived macrophages and THP-1 cells.…”

“…On the contrary, Rumora et al. ( 22 , 23 ) found that cigarette smoke was an activated factor of NLRP3 inflammasome in human monocyte-derived macrophages and THP-1 cells.…”

“…Cigarette smoke could enhance the NLRP3 inflammasome activation, and further promote the downstream inflammatory cytokines' release (including IL-1b and IL-18) in human bronchial epithelial cells (23,24), and human alveolar epithelial cells (26). Of note, inducing factors of acute exacerbations varied in different studies, such as lipopolysaccharide (23,26), lipoteichoic acid (23), extracellular heat shock protein 70 (23), and influenza A virus (24) etc. In addition, Rotta et al (36) verified that there was an upregulation of the NLRP3 in murine macrophage cells and human alveolar macrophages from Nontypeable Haemophilus Influenzae infection (NTHi)-induced AECOPD disease model, which imitated the pathogenesis of bacterial exacerbations in COPD.…”

“…Previous studies also proved that the activation of NLRP3 inflammasome was involved in the pathogenesis of AECOPD. Cigarette smoke could enhance the NLRP3 inflammasome activation, and further promote the downstream inflammatory cytokines’ release (including IL-1β and IL-18) in human bronchial epithelial cells ( 23 , 24 ), and human alveolar epithelial cells ( 26 ). Of note, inducing factors of acute exacerbations varied in different studies, such as lipopolysaccharide ( 23 , 26 ), lipoteichoic acid ( 23 ), extracellular heat shock protein 70 ( 23 ), and influenza A virus ( 24 ) etc.…”

“…A growing number of studies demonstrated that there were significant increases of NLRP3 and IL-1β in human peripheral blood mononuclear cells from AECOPD patients ( 23 , 30 ). Furthermore, potential NLRP3 inflammasome activation accompanied with inflammation cytokine release were also observed in human bronchial tissues ( 30 , 36 ), serum ( 30 ), BALF ( 30 ), sputum ( 33 ), and plasma ( 33 ).…”