Journal Article

Caspase-8 mediates inflammation and disease in rodent malaria

Lien, Egil, Pereira, Dhelio B., Pereira, Larissa M. N., Assis, Patrícia A., Junqueira, Caroline, Ataíde, Marco Antônio, Gazzinelli, Ricardo T., de Araújo, Natalia M., Golenbock, Douglas T., Durso, Danielle F., Zamboni, Dario S., Fitzgerald, Katherine A.

2020

Overview

Earlier studies indicate that either the canonical or non-canonical pathways of inflammasome activation have a limited role on malaria pathogenesis. Here, we report that caspase-8 is a central mediator of systemic inflammation, septic shock in the Plasmodium chabaudi -infected mice and the P . berghei -induced experimental cerebral malaria (ECM). Importantly, our results indicate that the combined deficiencies of caspases-8/1/11 or caspase-8/gasdermin-D (GSDM-D) renders mice impaired to produce both TNFα and IL-1β and highly resistant to lethality in these models, disclosing a complementary, but independent role of caspase-8 and caspases-1/11/GSDM-D in the pathogenesis of malaria. Further, we find that monocytes from malaria patients express active caspases-1, -4 and -8 suggesting that these inflammatory caspases may also play a role in the pathogenesis of human disease. Inflammasome activation plays a role in malaria pathogenesis, but details aren’t well understood. Here, the authors show that caspase-8 is a central mediator of systemic inflammation in rodent malaria and that monocytes from malaria patients express active caspases-1, -4 and -8.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/21 / 13/31 / 38/91 / 631/250/255 / 631/250/256 / 631/326/417/2546 / 64/60 / 692/699/255/1629 / 82/1 / 82/29 / Activation / Animals / Brain - pathology / Caspase 1 - metabolism / Caspase 8 - metabolism / Caspase-8 / Dendritic Cells - metabolism / Enzyme Activation / Extracellular Matrix - metabolism / Gene Expression Regulation / Humanities and Social Sciences / Humans / IL-1β / Inflammasomes / Inflammation / Inflammation - pathology / Interferon-gamma - metabolism / Interleukin-1beta - metabolism / Lethality / Lipopolysaccharides / Malaria / Malaria, Cerebral - enzymology / Malaria, Cerebral - genetics / Mice, Inbred C57BL / Monocytes / Monocytes - metabolism / multidisciplinary / Pathogenesis / Plasmodium chabaudi - physiology / Rodents / Science / Science (multidisciplinary) / Septic shock / Spleen - metabolism / Toll-Like Receptors - metabolism / Tumor necrosis factor-α / Vector-borne diseases