Potential Targets to Mitigate Trauma- or Sepsis-Induced Immune Suppression

Bergmann, Christian B; Beckmann, Nadine; Salyer, Christen E; Hanschen, Marc; Crisologo, Peter A.; Caldwell, Charles C.

doi:10.3389/fimmu.2021.622601

Cited by 23 publications

(22 citation statements)

References 161 publications

(343 reference statements)

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“…For the AR, ER, TGFβ, and NFκB pathways putative roles in sepsis have been described, generally in relation to specific immune cell types [42], [43], [44], [45], [46]. Immune cell-specific regulation of pathway activity is a likely explanation for lack of sufficient diagnostic power of som of the measured STPs when measured in whole blood samples with its intrinsic heterogeneity in immune cell composition.…”

Section: Several Signaling Pathway Activities Are Increased In Whole Blood From Patients With Sepsis: Potential For Diagnostic Usementioning

confidence: 99%

“…Despite the disadvantage of measuring in heterogeneic whole blood samples, the diagnostic performance of AR and TGFβ assays for sepsis was good. With respect to the TGFβ pathway, either decreased or elevated levels of various TGFβ pathway ligands have been reported in sepsis patients, while uncertainty remains with respect to the causal role of this pathway [46].…”

Section: Is There a Causal Relation Between Ar Pathway Activity And Sepsis?mentioning

confidence: 99%

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Androgen receptor pathway activity assay for sepsis diagnosis and prediction of favorable prognosis

Bouwman

Verhaegh

Stolpe

2021

Preprint

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IntroductionSepsis is a life-threatening complication of a bacterial infection. It is hard to predict which patients with a bacterial infection will develop sepsis, and accurate and timely diagnosis, as well as assessment of prognosis, is difficult. Aside from antibiotics-based treatment of the causative infection and circulation-supportive measures, treatment options remain limited. Better understanding of the immuno-pathophysiology of sepsis may lead to improved diagnostic and therapeutic solutions.Functional activity of the innate (inflammatory) and adaptive immune response is controlled by a dedicated set of cellular signal transduction pathways in the various immune cell types. To develop an immune response-based diagnostic assay for sepsis and provide novel therapeutic targets, signal transduction pathway activities were analyzed in whole blood samples from patients with sepsis.MethodsA validated and previously published set of signal transduction pathway (STP) assays, determining immune cell function, was used to analyze public Affymetrix expression microarray data from clinical studies containing data from pediatric and adult patients with sepsis. STP assays enable quantitative measurement of STP activity on individual patient sample data, and were used to calculate activity of androgen receptor (AR), estrogen receptor (ER), JAK-STAT1/2, JAK-STAT3, Notch, Hedgehog, TGFβ, FOXO-PI3K, MAPK-AP1, and NFκB signal transduction pathways.ResultsActivity of AR and TGFβ pathways was increased in children and adults with sepsis. Using the mean plus two standard deviations of normal pathway activity (in healthy individuals) as threshold, diagnostic assay parameters were determined. For diagnosis of pediatric sepsis, the AR pathway assay showed high sensitivity (77%) and specificity (97%), with a PPV of 99% and NPV of 50%. For prediction of favorable prognosis (survival), PPV was 95%, NPV was 21%. The TGFβ pathway activity assay performed slightly less for diagnosing sepsis, with a sensitivity of 64% and specificity of 98% (PPV 99%, NPV 39%).ConclusionThe AR and TGFβ pathways have an immunosuppressive role, suggesting a causal relation between increased pathway activity and sepsis immunopathology. STP assays have been converted to qPCR assays for further evaluation of clinical utility for sepsis diagnosis and prediction of prognosis, as well as for prediction of risk at developing sepsis in patients with a bacterial infection. STPs may present novel therapeutic targets in sepsis.

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Section: Several Signaling Pathway Activities Are Increased In Whole Blood From Patients With Sepsis: Potential For Diagnostic Usementioning

confidence: 99%

Section: Is There a Causal Relation Between Ar Pathway Activity And Sepsis?mentioning

confidence: 99%

Androgen receptor pathway activity assay for sepsis diagnosis and prediction of favorable prognosis

Bouwman

Verhaegh

Stolpe

2021

Preprint

View full text Add to dashboard Cite

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“…Immunosuppressive IL-10 cytokine commonly supports sepsis-induced immunosuppression (48) and its levels increase in mouse MDSCs as sepsis progresses to the later, protracted stage (13). IL-10 supports S100A9 protein translocation to the nucleus in MDSCs (36), concomitant with Hotairm1 binding to S100A9 (18).…”

Section: Discussionmentioning

confidence: 99%

Inhibiting KDM6A Demethylase Represses Long Non-Coding RNA Hotairm1 Transcription in MDSC During Sepsis

et al. 2022

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Myeloid-derived suppressor cells (MDSCs) prolong sepsis by promoting immunosuppression. We reported that sepsis MDSC development requires long non-coding RNA Hotairm1 interactions with S100A9. Using a mouse model that simulates the immunobiology of sepsis, we find that histone demethylase KDM6A promotes Hotairm1 transcription by demethylating transcription repression H3K27me3 histone mark. We show that chemical targeting of KDM6A by GSK-J4 represses Hotairm1 transcription, which coincides with decreases in transcription activation H3K4me3 histone mark and transcription factor PU.1 binding to the Hotairm1 promoter. We further show that immunosuppressive IL-10 cytokine promotes KDM6A binding at the Hotairm1 promoter. IL-10 knockdown repletes H3K27me3 and reduces Hotairm1 transcription. GSK-J4 treatment also relocalizes nuclear S100A9 protein to the cytosol. To support translation to human sepsis, we demonstrate that inhibiting H3K27me3 demethylation by KDM6A ex vivo in MDSCs from patients with protracted sepsis decreases Hotairm1 transcription. These findings suggest that epigenetic targeting of MDSCs in human sepsis might resolve post-sepsis immunosuppression and improve sepsis survival.

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“…Despite the disadvantage of measuring in whole blood samples, the diagnostic performance of AR and TGFβ assays for sepsis was good. With respect to the TGFβ pathway, either decreased or elevated levels of various TGFβ pathway ligands have been reported in sepsis patients, while uncertainty remains with respect to the causal role of this pathway ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

“…For the AR, ER, TGFβ, and NFκB pathways putative roles in sepsis have been described, generally in relation to specific immune cell types (40)(41)(42)(43)(44). This may explain the lack of diagnostic power of some of the measured STPs when measured in whole blood samples, since whole blood samples consist of a mix of multiple immune cell types.…”

Section: Activity Of Several Signaling Pathways Is Increased In Whole Blood From Patients With Sepsis: Potential For Diagnostic Usementioning

confidence: 99%

Androgen Receptor Pathway Activity Assay for Sepsis Diagnosis and Prediction of Favorable Prognosis

2021

View full text Add to dashboard Cite

Introduction: Sepsis is a life-threatening complication of a bacterial infection. It is hard to predict which patients with a bacterial infection will develop sepsis, and accurate and timely diagnosis as well as assessment of prognosis is difficult. Aside from antibiotics-based treatment of the causative infection and supportive measures, treatment options have remained limited. Better understanding of the immuno-pathophysiology of sepsis is expected to lead to improved diagnostic and therapeutic solutions.Functional activity of the innate (inflammatory) and adaptive immune response is controlled by a dedicated set of cellular signal transduction pathways, that are active in the various immune cell types. To develop an immune response-based diagnostic assay for sepsis and provide novel therapeutic targets, signal transduction pathway activities have been analyzed in whole blood samples from patients with sepsis.Methods: A validated and previously published set of signal transduction pathway (STP) assays, enabling determination of immune cell function, was used to analyze public Affymetrix expression microarray data from clinical studies containing data from pediatric and adult patients with sepsis. STP assays enable quantitative measurement of STP activity on individual patient sample data, and were used to calculate activity of androgen receptor (AR), estrogen receptor (ER), JAK-STAT1/2, JAK-STAT3, Notch, Hedgehog, TGFβ, FOXO-PI3K, MAPK-AP1, and NFκB signal transduction pathways.Results: Activity of AR and TGFβ pathways was increased in children and adults with sepsis. Using the mean plus two standard deviations of normal pathway activity (in healthy individuals) as threshold for abnormal STP activity, diagnostic assay parameters were determined. For diagnosis of pediatric sepsis, the AR pathway assay showed high sensitivity (77%) and specificity (97%), with a positive prediction value (PPV) of 99% and negative prediction value (NPV) of 50%. For prediction of favorable prognosis (survival), PPV was 95%, NPV was 21%. The TGFβ pathway activity assay performed slightly less for diagnosing sepsis, with a sensitivity of 64% and specificity of 98% (PPV 99%, NPV 39%).Conclusion: The AR and TGFβ pathways have an immunosuppressive role, suggesting a causal relation between increased pathway activity and sepsis immunopathology. STP assays have been converted to qPCR assays for further evaluation of clinical utility for sepsis diagnosis and prediction of prognosis, as well as for prediction of risk at developing sepsis in patients with a bacterial infection. STPs may present novel therapeutic targets in sepsis.

show abstract

Potential Targets to Mitigate Trauma- or Sepsis-Induced Immune Suppression

Cited by 23 publications

References 161 publications

Androgen receptor pathway activity assay for sepsis diagnosis and prediction of favorable prognosis

Androgen receptor pathway activity assay for sepsis diagnosis and prediction of favorable prognosis

Inhibiting KDM6A Demethylase Represses Long Non-Coding RNA Hotairm1 Transcription in MDSC During Sepsis

Androgen Receptor Pathway Activity Assay for Sepsis Diagnosis and Prediction of Favorable Prognosis

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