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

Abstract

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.

Functional and Evolutionary Analyses Identify Proteolysis as a General Mechanism for NLRP1 Inflammasome Activation

“…Rather, we expect that each NLRP1 linker has evolved to be recognized and cleaved by a unique protease (or set of proteases) from pathogens that are specific to a particular host. Consistent with the idea that mammalian hosts can detect the proteolytic activity of pathogen-encoded virulence factors, it was recently reported that the SpeB protease of group A Streptococcus can be detected through direct cleavage of IL-1β [50]. …”

Group A streptococcal M protein activates the NLRP3 inflammasome

“…Both canonical NLRP3 inflammasome and non-canonical (bacterial protease-induced) IL-1β signaling occur in macrophages responding to a GAS encounter 35 . Our studies indicate that the classical GAS virulence factor M1 protein makes an independent and important contribution to GAS NLRP3 inflammasome activation, IL-1β processing, and macrophage pyroptosis, thereby joining pore-forming toxin SLO 26 and ADP-ribosylating toxin SpyA 27 as known inflammasome activators produced by the pathogen.…”

“…Since IL-1R deficiency in mice 36 or treatment with IL-1R antagonist Anakinra in mice or humans 35 increase susceptibility to severe GAS infection, NLRP3 detection of M1 protein and other GAS factors appears on balance to serve a critical role in host defense against the organism. However, during advanced stages of systemic infection with invasive M1 GAS, IL-1β release and pyroptosis elicited by M1 may contribute to hyperinflammation and associated pathologies 10,13,15 .…”

Group A streptococcal pharyngitis: Immune responses involved in bacterial clearance and GAS-associated immunopathologies

“…With the use of macrophages deficient in inflammasome components, it was shown that both Nlrp3 and apoptosis‐associated speck‐like protein containing a caspase activation and recruitment domain were crucial for caspase‐1 activation and IL‐1β secretion during GAS infection. The membrane‐bound GAS virulence factor SpyA, an ADP‐ribosyltransferase, has also been shown to stimulate caspase‐1‐dependent inflammatory responses and IL‐1β production in murine macrophages, whereas the GAS virulence factor SpeB has been proposed to function as an inflammatory caspase mimic to cleave pro‐IL‐1β to generate mature IL‐1β . This suggests that GAS can generate active IL‐1β via multiple mechanisms.…”

“…The membrane-bound GAS virulence factor SpyA, an ADP-ribosyltransferase, has also been shown to stimulate caspase-1-dependent inflammatory responses and IL-1 production in murine macrophages, 83 whereas the GAS virulence factor SpeB has been proposed to function as an inflammatory caspase mimic to cleave pro-IL-1 to generate mature IL-1 . 84 This suggests that GAS can generate active IL-1 via multiple mechanisms. Another study using human macrophages showed that following stimulation with live or inactivated M1 GAS, inflammasome activation mediates the maturation of pro-IL-1 into mature-IL-1 .…”