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Differential impact of inflammasome-induced extracellular vesicles on immune cells: key control by the functional state of the recipient cell

Inflammasomes are cytoplasmic multiprotein complexes that survey the cytosol of immune cells for pathogen contamination or cellular perturbation by sensing stimuli that activate an inflammatory response and integrating their downstream signaling (1). They act as innate immune sensors and, in response to pathogens/cell damage, trigger pyroptosis, a lytic form of programmed cell death. The term “inflammasome” has been originally coined by Martinon et al. in 2002 who reported the assembly of cytosolic complexes which lead to proteolytic activation of caspases and inflammation (2). Inflammasomes consist of a sensor protein (NLRC4, NLRP or AIM2 protein), an inflammatory caspase, and in some cases an adaptor protein, such as ASC (the adaptor molecule apoptosis-associated speck-like protein containing a CARD). Inflammasomes are activated by a multiplicity of pathogen-derived or endogenous factors, often in an inflammasome-specific fashion (e.g., NLRP1 or NLRC4 activation by anthrax lethal toxin or bacterial flagellin, respectively). The inflammasome subtype most frequently involved in inflammation is NLRP3, typically activated by agents that form plasma membrane pores (e.g., nigericin or extracellular ATP) and thus cause a large intracellular K efflux. Once assembled and activated, the NLRP3 inflammasome triggers pro-caspase-1 cleavage, which generates the enzymatically active caspase-1 that in turn drives the enzymatic activation of the pro-inflammatory cytokines IL-1β and IL-18, as well as of gasdermins, a family of pore-forming effector proteins (Figure 1). Gasdermins have a homologous N-terminal gasdermin domain, which upon proteolytic removal of the inhibitory C-terminal domain forms a pore in the plasma membrane that causes membrane permeabilization, cell swelling and pyroptosis (3). Appropriate inflammasome activation is vital for the immune cells to cope with pathogens or tissue damage, but aberrant inflammasome activation is associated to uncontrolled tissue responses and various inflammatory diseases. Some inflammasome sensors, such as NLRP3, have been identified as drivers of chronic inflammatory pathologies. In particular, gain-of-function mutations in NLRP3 inflammasomes cause cryopyrin-associated periodic syndromes (CAPS) that are characterized by chronic systemic inflammation. Extracellular NLRP3 inflammasome oligomeric particles have been previously identified in the supernatant of activated macrophages and in the blood of CAPS patients (4). It has long been known that one of the functional consequence of inflammasome activation is the release of extracellular vesicles (EVs) from immune cells (5-8). EVs are heterogeneous membrane structures released by all cell types, which contain and transfer cellular components from a donor to a recipient cell and act as potent mediators of cell-to-cell communication. Immune cells-derived EVs, i.e., released by monocytes, microglia, dendritic cells and macrophages, were originally reported to serve as an Editorial Commentary