engleski

Interplay between extracellular Hsp70 and NLRP3 inflammasome in chronic obstructive pulmonary disease

Chronic obstructive respiratory disease (COPD) is a heterogeneous and complex disease characterized by airway obstruction and inflammation. Pathophysiology of COPD is associated with a long-term exposure to noxious particles and gases, particularly to cigarette smoke. Increasing evidence points to a key role of the innate immune system with its pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), in COPD. PRRs are capable of sensing different pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Under physiological conditions, DAMPs, such as adenosine triphosphate (ATP) or heat shock protein 70 (Hsp70), are mostly present intracellularly and are therefore hidden from recognition by the host immune system. However, under conditions of cellular stress or injury, these molecules are increasingly released into the extracellular environment and trigger sterile inflammation. PAMPs and DAMPs might be also recognized by intracellular PRRs, such as nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3). The NLRP3 inflammasome consists of a sensor (NLRP3), an adaptor (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC)) and an effector (caspase-1). Upon its activation, autoactivation of caspase-1 is triggered, thus promoting the maturation and secretion of interleukin (IL)-1β and IL-18. It has been shown that concentrations of extracellular Hsp70 (eHsp70) are increased in plasma of COPD patients. However, the mechanism underlying its pro-inflammatory effects in COPD is still unclear. In order to explore a possible interplay between eHsp70 and NLRP3 inflammasome in COPD we detected NLRP3 and IL-1β mRNA expression, and also ATP and IL-1β concentrations in supernatants of various cell lines and their primary cells counterparts after treatment with recombinant human (rh) Hsp70 protein and/or cigarette smoke extract (CSE). We also measured aforementioned parameters in blood samples of COPD patients in stable phase and age- and sex-matched healthy controls. Our findings suggested a possible involvement of eHsp70-induced activation of NLRP3 inflammasome in pathophysiology of COPD.

COPD, NLRP3, Hsp70

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