Abstract
Inflammasomes are innate immune sensors that regulate caspase-1 mediated inflammation in response to environmental, host- and pathogen-derived factors. The NLRP3 inflammasome is highly versatile as it is activated by a diverse range of stimuli. However, excessive or chronic inflammasome activation and subsequent interleukin-1β (IL-1β) release are implicated in the pathogenesis of various autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and diabetes. Accordingly, inflammasome inhibitor therapy has a therapeutic benefit in these diseases. In contrast, NLRP3 inflammasome is an important defense mechanism against microbial infections. IL-1β antagonizes bacterial invasion and dissemination. Unfortunately, patients receiving IL-1β or inflammasome inhibitors are reported to be at a disproportionate risk to experience invasive bacterial infections including pneumococcal infections. Pneumococci are typical colonizers of immunocompromised individuals and a leading cause of community-acquired pneumonia worldwide. Here, we summarize the current limited knowledge of inflammasome activation in pneumococcal infections of the respiratory tract and how inflammasome inhibition may benefit these infections in immunocompromised patients.
Highlights
The human innate immunity axis plays a pivotal role in detection of pathogen- or damageassociated molecular patterns (PAMPs and DAMPs) and contributes to a crucial inflammatory response
Studies in aged mice have suggested that an increase in endoplasmic reticulum stress and enhanced unfolded protein responses contribute to diminished assembly and activation of the NLR and pyrin domain containing receptor 3 (NLRP3) resulting in failed clearance of pneumococci [101]
The disproportionate gasdermin-D mediated cell membrane rupture in a variety of lung cells may result in a release of plethora of alarmins, including processed antigens, ATP, HMGB1, reactive oxygen species, cytokines, and chemokines [105]
Summary
The human innate immunity axis plays a pivotal role in detection of pathogen- or damageassociated molecular patterns (PAMPs and DAMPs) and contributes to a crucial inflammatory response. A wide range of stimuli including bacterial pore forming toxins can activate the NLRP3 inflammasome [5]. Common activators of the NLRP3 inflammasome are pathogens [17], extracellular ATP [18], pathogen associated RNA, proteins and toxins [5, 19, 20], heme [21], endogenous factors (amyloid-b, cholesterol crystals, uric acid crystals) [22,23,24], and environmental factors (silica and aluminum salts) [24, 25]. A variety of mechanisms, including AIM2 inflammasome activation, which plays a crucial role in bacterial detection, can result in production and release of IL-1b [reviewed in [56]].
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