title: Type I interferon signaling regulates activation of the absent in melanoma 2 inflammasome during Streptococcus pneumoniae infection.
abstract: Streptococcus pneumoniae, a Gram-positive bacterial pathogen, causes pneumonia, meningitis, and septicemia. Innate immune responses are critical for the control and pathology of pneumococcal infections. It has been demonstrated that S. pneumoniae induces the production of type I interferons (IFNs) by host cells and that type I IFNs regulate resistance and chemokine responses to S. pneumoniae infection in an autocrine/paracrine manner. In this study, we examined the effects of type I IFNs on macrophage proinflammatory cytokine production in response to S. pneumoniae. The production of interleukin-18 (IL-18), but not other cytokines tested, was significantly decreased by the absence or blockade of the IFN-α/β receptor, suggesting that type I IFN signaling is necessary for IL-18 production. Type I IFN signaling was also required for S. pneumoniae-induced activation of caspase-1, a cysteine protease that plays a central role in maturation and secretion of IL-18. Earlier studies proposed that the AIM2 and NLRP3 inflammasomes mediate caspase-1 activation in response to S. pneumoniae. From our results, the AIM2 inflammasome rather than the NLRP3 inflammasome seemed to require type I IFN signaling for its optimal activation. Consistently, AIM2, but not NLRP3, was upregulated in S. pneumoniae-infected macrophages in a manner dependent on the IFN-α/β receptor. Furthermore, type I IFN signaling was found to contribute to IL-18 production in pneumococcal pneumonia in vivo. Taken together, these results suggest that type I IFNs regulate S. pneumoniae-induced activation of the AIM2 inflammasome by upregulating AIM2 expression. This study revealed a novel role for type I IFNs in innate responses to S. pneumoniae.
authors.affiliation: Department of Microbiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Rendong
authors.initials: R
authors.lastname: Fang
authors.forename: Hideki
authors.initials: H
authors.lastname: Hara
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Sakai
authors.forename: Eduardo
authors.initials: E
authors.lastname: Hernandez-Cuellar
authors.forename: Masao
authors.initials: M
authors.lastname: Mitsuyama
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kawamura
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Tsuchiya
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005260:Female; D007113:Immunity, Innate / Q000502:physiology; D058847:Inflammasomes / Q000502:physiology*; D007370:Interferon Type I / Q000502:physiology*; D020382:Interleukin-18 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism*; D011008:Pneumococcal Infections / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013296:Streptococcus pneumoniae
chemical_list: C540422:Aim2 protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D007370:Interferon Type I; D020382:Interleukin-18; D009687:Nuclear Proteins; D020170:Caspase 1