A Novel Mechanism of Immunosuppression in Sepsis: Depletion of Monocytes and Macrophages

  • Li, Zhenyu (PI)
  • Morris, Peter (CoI)
  • Wei, Yinan (CoPI)
  • Li, Xiangan (Former CoI)

Grants and Contracts Details


Sepsis is a life-threatening condition that affects more than 1 million patients a year in the United States. Growing evidence indicates that immunosuppression is a major driving force for mortality in sepsis. Macrophages play essential roles in immune response to pathogens. While depletion of T, B, and dendritic cells has been identified in septic patients, whether macrophages are depleted in sepsis remains to be determined. In this proposal, we provide convincing evidence that i.p. injection of E. coli or cecal ligation and puncture (CLP) treatment in mice induced peripheral monocyte depletion and macrophage death in tissues. Recent in vitro studies showed that inflammasome activation elicited by Gram-negative bacteria involves multiple mechanisms, including noncanonical inflammasome activation and pyroptosis by intracellular LPS and canonical inflammasome activation by flagellin and the rod protein of the type III secretion system (T3SS) (Fg. 1). We show that intravenous injection of flagellin or the rod proteins from several Gram-negative bacteria induced depletion of peripheral monocytes and macrophages in tissues. We further showed that mice pretreated with the E. coli T3SS rod protein EprJ or a sub-lethal dose of E. Coli impaired immune response of macrophages and increased mortality rate by subsequent challenge with E. coli. Based on our preliminary findings, we hypothesize that monocytes and macrophages are depleted during sepsis, which contributes to sepsis-induced immunosuppression. We have assembled a multidisciplinary team and established a variety of innovative models and assays to test this hypothesis. In Specific Aim 1, we will investigate the role of inflammasome activation and pyroptosis in monocyte/macrophage depletion during sepsis. We will use caspase 1, caspase 11, and caspase1/11 double knockout mice to determine whether inflammasome activation plays an important role in monocyte/macrophage depletion during sepsis. We will use Gsdmd wholebody and macrophage-specific knockout mice to determine whether pyroptosis plays a role in monocyte/macrophage depletion. In Specific Aim 2, we will elucidate the role of apoptosis in monocyte/macrophage depletion during sepsis. We will investigate whether caspase 8- or 3-dependent apoptosis contribute to monocyte/macrophage depletion during sepsis using caspase 8 and 3 deficient mice. In Specific Aim 3, we will identify the contribution of monocyte/macrophage depletion to immunosuppression during sepsis. We will use a combination of sepsis models combined with bacterial strains lacking T3SS rod proteins or/and flagellin to investigate the role of monocyte/macrophage depletion in immunosuppression during sepsis. Completion of the proposed studies will reveal a novel molecular mechanism of immunosuppression induced by Gram-negative bacteria. Such findings will significantly advance our understanding about the pathogenesis of sepsis and identify new drug targets for this deadly disease.
Effective start/end date9/20/1911/30/21


  • National Institute of General Medical Sciences: $753,318.00


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