Mechanisms and modulation of sepsis-induced immune dysfunction in children

Abstract

Summary paragraph/Abstract Immunologic responses during sepsis vary significantly among patients and evolve over the course of illness. Sepsis has a direct impact on the immune system due to adverse alteration of the production, maturation, function, and apoptosis of immune cells. Dysregulation in both the innate and adaptive immune responses during sepsis leads to a range of phenotypes consisting of both hyperinflammation and immunosuppression that can result in immunoparalysis. In this review, we discuss components of immune dysregulation in sepsis, biomarkers and functional immune assays to aid in immunophenotyping patients, and evolving immunomodulatory therapies. Important research gaps for the future include: 1) Defining how age, host factors including prior exposures, and genetics impact the trajectory of sepsis in children, 2) Developing tools for rapid assessment of immune function in sepsis, and 3) Assessing how evolving pediatric sepsis endotypes respond differently to immunomodulation. Although multiple promising immunomodulatory agents exist or are in development, access to rapid immunophenotyping will be needed to identify which children are most likely to benefit from which therapy. Advancements in the ability to perform multidimensional endotyping will be key to developing a personalized approach to children with sepsis.

The Regulatory Roles of Ezh2 in Response to Lipopolysaccharide (LPS) in Macrophages and Mice with Conditional Ezh2 Deletion with LysM-Cre System

“…Nevertheless, sepsis-induced immune exhaustion with secondary infection may become more common in patients with sepsis due to the improved supportive care for the maintenance of patients during hyper-inflammatory sepsis, which decreases mortality, especially in the early phase of sepsis [ 16 ]. Although several factors are mentioned as the cause of sepsis-induced immune exhaustion, including apoptotic death of several immune cells, myeloid-derived suppressor cells, and increased regulatory T cells, data on lipopolysaccharide (LPS) tolerance, which is defined as the decreased responses following secondary or prolonged LPS stimulation [ 17 , 18 , 19 , 20 ], are relatively more rare compared with other mechanisms.…”

NLRC3 expression in macrophage impairs glycolysis and host immune defense by modulating the NF-κB-NFAT5 complex during septic immunosuppression

“…Low HLA-DR expression and decreased levels of proinflammatory cytokines (e.g., tumor necrosis factor a [TNF-a]) in monocytes after sepsis are considered a hallmark of sepsis-induced immunosuppression. 5,27 These hallmarks were analyzed (Figures 1B-1D) and revealed an overall decrease in HLA-DR expression in monocytes from septic patients (Figures 1B and 1C), and the HLA-DR expression inversely correlated with induction of NLRC3 expression (r 2 = À0.5451, p = 0.0007; Figure 1F). Additionally, we observed significantly impaired production of TNF-a in monocytes challenged with LPS in vitro (Figure 1D), and the decreased TNF-a was inversely correlated with induction of NLRC3 expression (r 2 = À0.7132, p < 0.0004; Figure 1H).…”

The landscape of immune dysregulation in pediatric sepsis at a single-cell resolution

“…The utility of (monocyte) mHLA-DR expression in the periphery has been well established in diagnosis of adult sepsis with a threshold < 30 % to be linked with increased mortality 46 , meanwhile similar threshold might not be applicable in pediatric sepsis 47 . Our data illustrated an enhanced HLA-DR expression in adult sepsis compared to pediatric sepsis, indicating that such a threshold could be even lower in pediatrics.…”