Research ArticleSepsis

Identification of tetranectin-targeting monoclonal antibodies to treat potentially lethal sepsis

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Science Translational Medicine  15 Apr 2020:
Vol. 12, Issue 539, eaaz3833
DOI: 10.1126/scitranslmed.aaz3833

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Got to keep them separated

Sepsis, potentially lethal organ dysfunction caused by infection, remains a major problem. By investigating the mechanisms of inflammation in sepsis, Chen et al. determined that an antibody blocking the interaction between two proteins may provide a useful intervention. One of these proteins, tetranectin, is depleted in patients with sepsis and associated with better survival in mouse models. The other protein, HMGB1, is a known mediator of sepsis. The authors found that HMGB1 binds tetranectin, resulting in endocytosis of both proteins and worsening inflammation, whereas an antibody blocking this interaction can be protective. A related Focus by Paterson et al. discusses the implications of these findings.

Abstract

For the clinical management of sepsis, antibody-based strategies have only been attempted to antagonize proinflammatory cytokines but not yet been tried to target harmless proteins that may interact with these pathogenic mediators. Here, we report an antibody strategy to intervene in the harmful interaction between tetranectin (TN) and a late-acting sepsis mediator, high-mobility group box 1 (HMGB1), in preclinical settings. We found that TN could bind HMGB1 to reciprocally enhance their endocytosis, thereby inducing macrophage pyroptosis and consequent release of lactate dehydrogenase and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain. The genetic depletion of TN expression or supplementation of exogenous TN protein at subphysiological doses distinctly affected the outcomes of potentially lethal sepsis, revealing a previously underappreciated beneficial role of TN in sepsis. Furthermore, the administration of domain-specific polyclonal and monoclonal antibodies effectively inhibited TN/HMGB1 interaction and endocytosis and attenuated the sepsis-induced TN depletion and tissue injury, thereby rescuing animals from lethal sepsis. Our findings point to a possibility of developing antibody strategies to prevent harmful interactions between harmless proteins and pathogenic mediators of human diseases.

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