Inflammasome Activators Induce Interleukin-1α Secretion via Distinct Pathways with Differential Requirement for the Protease Function of Caspase-1

Abstract

Through their capacity to sense danger signals and to generate active interleukin-1β (IL-1β), inflammasomes occupy a central role in the inflammatory response. In contrast to IL-1β, little is known about how IL-1α is regulated. We found that all inflammasome activators also induced the secretion of IL-1α, leading to the cosecretion of both IL-1 cytokines. Depending on the type of inflammasome activator, release of IL-1α was inflammasome dependent or independent. Calcium influx induced by the opening of cation channels was sufficient for the inflammasome-independent IL-1α secretion. In both cases, IL-1α was released primarily in a processed form, resulting from intracellular cleavage by calpain-like proteases. Inflammasome-caspase-1-dependent release of IL-1α and IL-1β was independent of caspase-1 catalytic activity, defining a mode of action for caspase-1. Because inflammasomes contribute to the pathology of numerous chronic inflammatory diseases such as gout and diabetes, IL-1α antagonists may be beneficial in the treatment of these disorders.

Distinct Contributions of Interleukin-1α (IL-1α) and IL-1β to Innate Immune Recognition of Pseudomonas aeruginosa in the Lung

“…Recent studies have shown that myeloid cells secrete IL-1␣ in response to many classical inflammasome activators (9,14). These responses are dependent on canonical inflammasome components and result in the cosecretion of IL-1␣ and cleaved IL-1␤; however, particulate NLRP3 activators also induced inflammasome-independent IL-1␣ secretion in one study (14).…”

“…These responses are dependent on canonical inflammasome components and result in the cosecretion of IL-1␣ and cleaved IL-1␤; however, particulate NLRP3 activators also induced inflammasome-independent IL-1␣ secretion in one study (14). Even in the absence of IL-1␣ secretion, however, bioactive, surface-bound IL-1␣ is produced by monocytes solely in response to NF-Bactivating signals and does not require inflammasome components, caspase-1, or IL-1␤ (9).…”

Pneumolysin-Dependent Calpain Activation and Interleukin-1α Secretion in Macrophages Infected with Streptococcus pneumoniae

“…We and others previously suggested that S. pneumoniae cells internalized by macrophages underwent rapid death and released PLY, thereby destabilizing phagosomal membranes in a PLY-dependent manner (11,35). Interestingly, phagosomal destabilization by particulate NLRP3 activators has been proposed to facilitate the production of IL-1␣ independently of the inflammasome machinery (30). From those observations, it is also conceivable that PLY released from internalized pneumococci promotes IL-1␣ production through the destabilization of phagosomal membranes.…”

“…It was reported previously that several inflammasome activators induce the maturation and secretion of IL-1␣ in a manner dependent on inflammasome components, including ASC (apoptosis-associated speck-like protein containing a CARD [caspase activation and recruitment domain]) and caspase-1 (30)(31)(32)(33). We previously reported that in S. pneumoniae-infected macrophages, the AIM2 and NLRP3 inflammasomes play a critical role in caspase-1 activation and the subsequent processing and secretion of IL-18 and IL-1␤ (11).…”

Small-Volume Adenosine, Lidocaine, and Mg 2+ 4-Hour Infusion Leads to 88% Survival after 6 Days of Experimental Sepsis in the Rat without Antibiotics

“…4) is unclear, because this cytokine (and IL-18) is part of the IL-1 family that is also activated by the innate caspase-1 inflammasome complex (31). The reason may be that IL-1␤ activation and IL-1␣ activation require different pattern recognition "trigger"' signals or compartmentation strategies to feed their specific precursors into the inflammasome complex (32) or may involve other independent activation pathways (33), such as platelets which produce IL-1␤ (25).…”