Inflammasome Activation in an In Vitro Sepsis Model Recapitulates Increased Monocyte Distribution Width Seen in Patients With Sepsis

Eisinger, Gregory; Osman, Wissam; Prather, Evan R.; Julián, M; Gavrilin, Mikhail A.; Crouser, Elliott D.; Wewers, Mark D.

doi:10.1097/cce.0000000000000631

Cited by 8 publications

(5 citation statements)

References 10 publications

(14 reference statements)

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“…In severe COVID-19, inflammatory monocyte signatures predominate and delayed or impaired type I interferon (IFN) production contribute to increased levels of IL-6 and subsequent cytokine storm (35, 36). In contrast, immune responses in patients with mild disease are characterized by rapid-onset type I IFN production with subsequent induction of interferon-stimulated genes, ultimately resulting in the inhibition of viral replication (37). While the impact of IFN signaling on monocyte anisocytosis has not been described, others have suggested that increased MDW reflects inflammasome activation or myeloid suppression as a result of viral infection (38).…”

Section: Discussionmentioning

confidence: 99%

Monocyte anisocytosis corresponds with increasing severity of COVID-19 in children

et al. 2023

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IntroductionAlthough SARS-CoV-2 infection can lead to severe COVID-19 in children, the role of biomarkers for assessing the risk of progression to severe disease is not well established in the pediatric population. Given the differences in monocyte signatures associated with worsening COVID-19 in adults, we aimed to determine whether monocyte anisocytosis early in the infectious course would correspond with increasing severity of COVID-19 in children.MethodsWe performed a multicenter retrospective study of 215 children with SARS-CoV-2 infection, Multisystem Inflammatory Syndrome in Children (MIS-C), convalescent COVID-19, and healthy age-matched controls to determine whether monocyte anisocytosis, quantified by monocyte distribution width (MDW) on complete blood count, was associated with increasing severity of COVID-19. We performed exploratory analyses to identify other hematologic parameters in the inflammatory signature of pediatric SARS-CoV-2 infection and determine the most effective combination of markers for assessing COVID-19 severity in children.ResultsMonocyte anisocytosis increases with COVID-19 severity and need for hospitalization. Although other inflammatory markers such as lymphocyte count, neutrophil/lymphocyte ratio, C-reactive protein, and cytokines correlate with disease severity, these parameters were not as sensitive as MDW for identifying severe disease in children. An MDW threshold of 23 offers a sensitive marker for severe pediatric COVID-19, with improved accuracy when assessed in combination with other hematologic parameters.ConclusionMonocyte anisocytosis corresponds with shifting hematologic profiles and inflammatory markers in children with COVID-19, and MDW serves as a clinically accessible biomarker for severe COVID-19 in children.

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Section: Discussionmentioning

confidence: 99%

Monocyte anisocytosis corresponds with increasing severity of COVID-19 in children

et al. 2023

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“…Human monocytes are believed to be important mediators of human sepsis, which occurs when inflammatory responses to infection are so robust that they induce physiologic alterations in the host ( Fingerle et al, 1993 ; Stearns-Kurosawa et al, 2011 ). It has been proposed that monocyte pyroptosis mediates early inflammatory events which drive sepsis ( Eisinger et al, 2022 ). Rapid monocyte recruitment into peripheral tissues during microbial infection allows for the replenishment of local macrophage and DC populations ( Serbina et al, 2008 ).…”

Section: Mechanisms Enhancing Lps-mediated Activationmentioning

confidence: 99%

Caspase-4 and -5 Biology in the Pathogenesis of Inflammatory Bowel Disease

Smith

Creagh

2022

Front. Pharmacol.

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Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the gastrointestinal tract, associated with high levels of inflammatory cytokine production. Human caspases-4 and -5, and their murine ortholog caspase-11, are essential components of the innate immune pathway, capable of sensing and responding to intracellular lipopolysaccharide (LPS), a component of Gram-negative bacteria. Following their activation by LPS, these caspases initiate potent inflammation by causing pyroptosis, a lytic form of cell death. While this pathway is essential for host defence against bacterial infection, it is also negatively associated with inflammatory pathologies. Caspases-4/-5/-11 display increased intestinal expression during IBD and have been implicated in chronic IBD inflammation. This review discusses the current literature in this area, identifying links between inflammatory caspase activity and IBD in both human and murine models. Differences in the expression and functions of caspases-4, -5 and -11 are discussed, in addition to mechanisms of their activation, function and regulation, and how these mechanisms may contribute to the pathogenesis of IBD.

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“…Apoptosis and dysfunction of immune cells lead to the persistence of immunosuppression which may confer in a secondary infection in sepsis patients (van der Poll et al, 2017). Eisinger's team showed that monocyte distribution width (MDW) was increased in septic patients inferring the presence of swollen monocytes undergoing pyroptotic death (Eisinger et al, 2022). Different monocyte subsets exhibit distinct function in sepsis.…”

Section: Dysregulated Immune Response In Sepsismentioning

confidence: 99%

Immune dysregulation and RNA N6‐methyladenosine modification in sepsis

Chen

Zhang

et al. 2022

WIREs RNA

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Sepsis is defined as life-threatening organ dysfunction caused by the host immune dysregulation to infection. It is a highly heterogeneous syndrome with complex pathophysiological mechanisms. The host immune response to sepsis can be divided into hyper-inflammatory and immune-suppressive phases which could exist simultaneously. In the initial stage, systemic immune response is activated after exposure to pathogens. Both innate and adaptive immune cells undergo epigenomic, transcriptomic, and functional reprogramming, resulting in systemic and persistent inflammatory responses. Following the hyperinflammatory phase, the body is in a state of continuous immunosuppression, which is related to immune cell apoptosis, metabolic failure, and epigenetic reprogramming. Immunosuppression leads to increased susceptibility to secondary infections in patients with sepsis. RNA N6-Methyladenosine (m6A) has been recognized as an indispensable epitranscriptomic modification involved in both physiological and pathological processes. Recent studies suggest that m6A could reprogram both innate and adaptive immune cells through posttranscriptional regulation of RNA metabolism. Dysregulated m6A modifications contribute to the pathogenesis of immune-related diseases. In this review, we summarize immune cell changes and the potential role of m6A modification in sepsis.

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Inflammasome Activation in an In Vitro Sepsis Model Recapitulates Increased Monocyte Distribution Width Seen in Patients With Sepsis

Cited by 8 publications

References 10 publications

Monocyte anisocytosis corresponds with increasing severity of COVID-19 in children

Monocyte anisocytosis corresponds with increasing severity of COVID-19 in children

Caspase-4 and -5 Biology in the Pathogenesis of Inflammatory Bowel Disease

Immune dysregulation and RNA N6‐methyladenosine modification in sepsis

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