From Inflammasome to Exosome—Does Extracellular Vesicle Secretion Constitute an Inflammasome-Dependent Immune Response?

Abstract

Inflammasomes are intracellular protein complexes of pattern recognition receptors and caspase-1, with essential functions in regulating inflammatory responses of macrophages and dendritic cells. The primary role of inflammasomes is to catalyze processing and secretion of pro-inflammatory cytokines IL-1β and IL-18. Recently, intracellular non-canonical inflammasome activation by caspases-4/5, which are also regulators of pyroptosis via processing gasdermin D, has been elucidated. Caspase-1, the effector protease of inflammasome complex, is also known to modulate secretion of large number of other proteins. Thereby, besides its known role in processing pro-inflammatory cytokines, the inflammasome turns into a universal regulator of protein secretion, which allows the danger-exposed cells to release various proteins in order to alert and guide neighboring cells. Majority of these proteins are not secreted through the conventional ER-Golgi secretory pathway. Instead, they are segregated in membrane-enclosed compartment and secreted in nanosized extracellular vesicles, which protect their cargo and guide it for delivery. Growing evidence indicates that inflammasome activity correlates with enhanced secretion of extracellular vesicles and modulation of their protein cargo. This inflammasome-driven unconventional, vesicle-mediated secretion of multitude of immunoregulatory proteins may constitute a novel paradigm in inflammatory responses. In this mini review we discuss the current knowledge and highlight unsolved questions about metabolic processes, signals, and mechanisms linking inflammasome activity with regulated extracellular vesicle secretion of proteins. Further investigations on this relationship may in the future help understanding the significance of extracellular vesicle secretion in inflammatory diseases such as atherosclerosis, gouty arthritis, asthma, Alzheimer's and many others.

MicroRNA Profiling of Exosomes Derived from Red Blood Cell Units: Implications in Transfusion-Related Immunomodulation

“…They are the products of exocytosis; they contain DNA, coding or noncoding RNAs (ncRNAs), and protein fragments that are secreted by their parental cell and can be taken into the recipient cells. Exosomes are reported 2 BioMed Research International to carry out several physiological and pathophysiological functions during carcinogenesis and immunomodulation in both in vitro and in vivo conditions [12][13][14][15]. ncRNAs of the exosomes have been proved to play an important role in regulation of these procedures [14,15].…”

“…Exosomes are reported 2 BioMed Research International to carry out several physiological and pathophysiological functions during carcinogenesis and immunomodulation in both in vitro and in vivo conditions [12][13][14][15]. ncRNAs of the exosomes have been proved to play an important role in regulation of these procedures [14,15]. Danesh et al in their study have revealed that exosomes derived from RBC units could potentiate T-cell survival and mitogen-induced proliferation through antigen presenting cells (APCs), eventually contributing to TRIM [9].…”

Acquired Aplastic Anemia as a Clonal Disorder of Hematopoietic Stem Cells

“…Inflammaging is also characterized by release of microvesicles and exosomes from stressed or damaged cells [111]. These small circular membrane fragments that contain cell cytoplasma-derived mRNA, microRNA and proteins may be of diagnostic value [112,113].…”

Tumor‐derived exosomes (TDEs): How to avoid the sting in the tail

“…However, recent work suggests that increased NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activity, which plays a key role in innate immunity, can regulate EV secretion, with several reports demonstrating direct associations between NLRP3 inflammasome activation and enhanced exosome release rates and changes in exosome cargo compositions. 72 NLRP3 inflammasome polymorphisms are also associated with the development of certain cancers, including breast cancer, melanoma, and hepatocellular carcinoma (HCC), 73 and NLRP3 inflammasome inhibitors have been patented for potential cancer therapeutic applications. 74 The NLRP3 inflammasome is a multi-subunit cytosolic protein complexes that assembles upon exposure of its pattern recognition receptor, NLRP3, to a broad range of damage-associated molecular patterns or responses induced by them, including extracellular adenosine triphosphate (ATP), crystalline complexes and protein aggregates, mitochondrial dysfunction and lysosomal damage.…”

“…Multiple studies have examined TDE effects on tumor development and tumor microenvironment inflammation, as described in the following sections, but relatively few have examined how stress and proinflammatory tumor cell responses influence exosome secretion. However, recent work suggests that increased NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activity, which plays a key role in innate immunity, can regulate EV secretion, with several reports demonstrating direct associations between NLRP3 inflammasome activation and enhanced exosome release rates and changes in exosome cargo compositions . NLRP3 inflammasome polymorphisms are also associated with the development of certain cancers, including breast cancer, melanoma, and hepatocellular carcinoma (HCC), and NLRP3 inflammasome inhibitors have been patented for potential cancer therapeutic applications …”