Receptor-interacting protein kinase 3 deficiency inhibits immune cell infiltration and attenuates organ injury in sepsis.

Archna Sharma,Weng-Lang Yang,Zhimin Wang,Ping Wang,Shingo Matsuo

doi:10.1186/cc13970

Abstract

IntroductionSepsis is defined as a systemic hyper-inflammatory immune response, with a subsequent immune-suppressive phase, which leads to multiple organ dysfunction and late lethality. Receptor-interacting protein kinase 3 (RIPK3)-dependent necrosis is implicated in driving tumor necrosis factor alpha (TNF-α)- and sepsis-induced mortality in mice. However, it is unknown if RIPK3 deficiency has any impact on immune cell trafficking, which contributes to organ damage in sepsis.MethodsTo study this, male wild-type (WT) and RIPK3-deficient (Ripk3-/-) mice on C57BL/6 background were subjected to sham operation or cecal ligation and puncture (CLP)-induced sepsis. Blood and tissue samples were collected 20 hours post-CLP for various measurements.ResultsIn our severe sepsis model, the mean survival time of Ripk3-/- mice was significantly extended to 68 hours compared to 41 hours for WT mice. Ripk3-/- mice had significantly decreased plasma levels of TNF-α and IL-6 and organ injury markers compared to WT mice post-CLP. In the lungs, Ripk3-/- mice preserved better integrity of microscopic structure with reduced apoptosis, and decreased levels of IL-6, macrophage inflammatory protein (MIP)-2 and keratinocyte-derived chemokine (KC), compared to WT. In the liver, the levels of MIP-1, MIP-2 and KC were also decreased in septic Ripk3-/- mice. Particularly, the total number of neutrophils in the lungs and liver of Ripk3-/- mice decreased by 59.9% and 66.7%, respectively, compared to WT mice post-CLP. In addition, the number of natural killer (NK) and CD8T cells in the liver decreased by 64.8% and 53.4%, respectively, in Ripk3-/- mice compared to WT mice post-sepsis.ConclusionsOur data suggest that RIPK3 deficiency modestly protected from CLP-induced severe sepsis and altered the immune cell trafficking in an organ-specific manner attenuating organ injury. Thus, RIPK3 acts as a detrimental factor in contributing to the organ deterioration in sepsis.

Highlights

Sepsis is defined as a systemic hyper-inflammatory immune response, with a subsequent immune-suppressive phase, which leads to multiple organ dysfunction and late lethality
In this study, we demonstrate that Receptor-interacting protein kinase 3 (RIPK3) deficiency prolongs survival in severe septic mice induced by cecal ligation and puncture (CLP) and reduces systemic levels of pro-inflammatory cytokines as well as organ injury markers
We show that RIPK3 deficiency attenuates CLP-induced acute lung injury (ALI) resulting in improved integrity of lung architecture, reduced apoptotic cell death in lung epithelium, and decreased local pro-inflammatory cytokine and chemokine production

Summary

Introduction

Sepsis is defined as a systemic hyper-inflammatory immune response, with a subsequent immune-suppressive phase, which leads to multiple organ dysfunction and late lethality. Receptor-interacting protein kinase 3 (RIPK3)-dependent necrosis is implicated in driving tumor necrosis factor alpha (TNF-α)- and sepsis-induced mortality in mice. It is unknown if RIPK3 deficiency has any impact on immune cell trafficking, which contributes to organ damage in sepsis. Ripk3−/− mice had significantly decreased plasma levels of TNF-α and IL-6 and organ injury markers compared to WT mice post-CLP. RIPK3-dependent necrosis has been shown to be responsible for the mortality of septic mice induced either by TNF-α injection or polymicrobial sepsis, suggesting that targeting necrotic cells could be a novel and promising therapeutic approach for improving sepsis outcome [24,25]. Determining the effects of ablation of RIPK3mediated necrosis on the trafficking of various subtypes of immune cells and resultant organ injury following sepsis is critical for the development of therapies for patients

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