Constitutive Interferon Maintains GBP Expression Required for Release of Bacterial Components Upstream of Pyroptosis and Anti-DNA Responses

Publication date: 3 July 2018
Source:Cell Reports, Volume 24, Issue 1
Author(s): Beiyun C. Liu, Joseph Sarhan, Alexander Panda, Hayley I. Muendlein, Vladimir Ilyukha, Jörn Coers, Masahiro Yamamoto, Ralph R. Isberg, Alexander Poltorak
Legionella pneumophila elicits caspase-11-driven macrophage pyroptosis through guanylate-binding proteins (GBPs) encoded on chromosome 3. It has been proposed that microbe-driven IFN upregulates GBPs to facilitate pathogen vacuole rupture and bacteriolysis preceding caspase-11 activation. We show here that macrophage death occurred independently of microbial-induced IFN signaling and that GBPs are dispensable for pathogen vacuole rupture. Instead, the host-intrinsic IFN status sustained sufficient GBP expression levels to drive caspase-1 and caspase-11 activation in response to cytosol-exposed bacteria. In addition, endogenous GBP levels were sufficient for the release of DNA from cytosol-exposed bacteria, preceding the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway for Ifnb induction. Mice deficient for chromosome 3 GBPs were unable to mount a rapid IL-1/chemokine (C-X-C motif) ligand 1 (CXCL1) response during Legionella-induced pneumonia, with defective bacterial clearance. Our results show that rapid GBP activity is controlled by host-intrinsic cytokine signaling and that GBP activities precede immune amplification responses, including IFN induction, inflammasome activation, and cell death.

Graphical abstract

Teaser

Guanylate-binding proteins act upstream of many cytosolic pathogen sensors. It is assumed that infection-associated IFN signaling precedes GBP induction. Liu et al. find that host-intrinsic IFN signaling maintains GBPs in naive macrophages to mediate the disruption of cytosol-accessible bacteria. The findings elucidate a crucial role of tonic cytokines in maintaining immune readiness.


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