IL-1β is an innate immune sensor of microbial proteolysis

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Science Immunology  19 Aug 2016:
Vol. 1, Issue 2, pp. eaah3539
DOI: 10.1126/sciimmunol.aah3539

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A new trick for IL-1β

One strategy to tame the symptoms of autoimmune diseases such as rheumatoid arthritis is to block the pain-causing inflammation. For rheumatoid arthritis, one such therapy is the interleukin-1β (IL-1β) receptor antagonist anakinra; LaRock et al. have documented that patients who receive anakinra have an increased susceptibility to group A Streptococcus (GAS) infections. They found that GAS protease SpeB directly activates IL-1β independent of host inflammasome proteins and propose a new role for IL-1β as a sensor of GAS infection. This may account for more frequent GAS infections in rheumatoid arthritis patients receiving anakinra.


Interleukin-1β (IL-1β) is a key proinflammatory cytokine that drives antimicrobial immune responses. IL-1β is aberrantly activated in autoimmune diseases, and IL-1β inhibitors are used as therapeutic agents to treat patients with certain autoimmune disorders. Review of postmarketing surveillance of patients receiving IL-1β inhibitors found a disproportionate reporting of invasive infections by group A Streptococcus (GAS). IL-1β inhibition increased mouse susceptibility to GAS infection, but IL-1β was produced independent of canonical inflammasomes. Newly synthesized IL-1β 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-1β. During invasive infection, GAS isolates may acquire pathoadaptive mutations eliminating SpeB expression to evade detection by IL-1β. Pharmacological IL-1β inhibition alleviates this selective pressure, allowing invasive infection by nonpathoadapted GAS. Thus, IL-1β is a sensor that directly detects pathogen-associated proteolysis through an independent pathway operating in parallel with host inflammasomes. Because IL-1β 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.

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