IL-1β is an innate immune sensor of microbial proteolysis.
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.
Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California (UC), San Diego, La Jolla, CA 92093, USA.
Christopher N
CN
LaRock
Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California (UC), San Diego, La Jolla, CA 92093, USA.
Jordan
J
Todd
Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California (UC), San Diego, La Jolla, CA 92093, USA.
Doris L
DL
LaRock
Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California (UC), San Diego, La Jolla, CA 92093, USA.
Joshua
J
Olson
Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, La Jolla, CA 92093, USA.
Anthony J
AJ
O'Donoghue
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
Avril A B
AA
Robertson
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
Matthew A
MA
Cooper
Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California (UC), San Diego, La Jolla, CA 92093, USA.
Hal M
HM
Hoffman
Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California (UC), San Diego, La Jolla, CA 92093, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, La Jolla, CA 92093, USA.
Victor
V
Nizet