Citation

Interleukin-1b (IL-1b) is a key proinflammatory cytokine that drives antimicrobial immune responses. IL-1b is aberrantly activated in autoimmune diseases, and IL-1b inhibitors are used as therapeutic agents to treat patients with certain autoimmune disorders. Review of postmarketing surveillance of patients receiving IL-1b inhibitors found a disproportionate reporting of invasive infections by group A Streptococcus(GAS). IL-1b inhibition increased mouse susceptibility to GAS infection, but IL-1b was produced independent of canonical inflammasomes. Newly synthesized IL-1b has an amino-terminal prodomain that blocks signaling activity, which is usually proteolytically removed by caspase-1, a protease activated within the inflammasome structure. In place of host caspases, the secreted GAS cysteine protease SpeB generated mature IL-1b. During invasive infection, GAS isolates may acquire pathoadaptive mutations eliminating SpeB expression to evade detection by IL-1b. Pharmacological IL-1b inhibition alleviates this selective pressure, allowing invasive infection by nonpathoadapted GAS. Thus, IL-1b is a sensor that directly detects pathogen-associated proteolysis through an independent pathway operating in parallel with host inflammasomes. Because IL-1b function is maintained across species, yet cleavage by caspases does not appear to be, detection of microbial proteases may represent an ancestral system of innate immune regulation.