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Innate immune response against  Brucella abortus  involves activation of Toll-like receptors (TLRs) and NOD-like receptors (NLRs). Among the NLRs involved in the recognition of  B .  abortus  are NLRP3 and AIM2. Here, we demonstrate that  B .  abortus  triggers non-canonical inflammasome activation dependent on caspase-11 and gasdermin-D (GSDMD). Additionally, we identify that  Brucella -LPS is the ligand for caspase-11 activation. Interestingly, we determine that  B .  abortus  is able to trigger pyroptosis leading to pore formation and cell death, and this process is dependent on caspase-11 and GSDMD but independently of caspase-1 protease activity and NLRP3. Mice lacking either caspase-11 or GSDMD were significantly more susceptible to infection with  B .  abortus  than caspase-1 knockout or wild-type animals. Additionally, guanylate-binding proteins (GBPs) present in mouse chromosome 3 participate in the recognition of LPS by caspase-11 contributing to non-canonical inflammasome activation as observed by the response of  Gbp   chr3-/-   BMDMs to bacterial stimulation. We further determined by siRNA knockdown that among the GBPs contained in mouse chromosome 3, GBP5 is the most important for  Brucella  LPS to be recognized by caspase-11 triggering IL-1β secretion and LDH release. Additionally, we observed a reduction in neutrophil, dendritic cell and macrophage influx in spleens of  Casp11   -/-   and  Gsdmd   -/-   compared to wild-type mice, indicating that caspase-11 and GSDMD are implicated in the recruitment and activation of immune cells during  Brucella  infection. Finally, depletion of neutrophils renders wild-type mice more susceptible to  Brucella  infection. Taken together, these data suggest that caspase-11/GSDMD-dependent pyroptosis triggered by  B .  abortus  is important to infection restriction  in vivo  and contributes to immune cell recruitment and activation.

Guanylate-binding protein 5 licenses caspase-11 for Gasdermin-D mediated host resistance to Brucella abortus infection