Kidney injury enhances renal G-CSF expression and modulates granulopoiesis and human neutrophil CD177 <i>in vivo</i>

Volkmann, Julia; Schmitz, Jessica; Nordlohne, Johannes; Dong, Lei; Helmke, Alexandra; Immenschuh, Stephan; Bernhardt, Wanja M.; Gwinner, Wilfried; Bräsen, Jan Hinrich; Schmitt, Roland; Haller, Hermann; Vietinghoff, Sibylle von

doi:10.1111/cei.13372

Cited by 12 publications

(13 citation statements)

References 67 publications

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“…Particularly CD274 (PD-1L) was enriched in cluster 1 compared to cluster 2, supporting the potential of neutrophils to progress toward a suppressive phenotype in severe COVID-19 ( Figure S6 J). Interestingly, CD177 is expressed in pre-neutrophils and persisting in cluster 1 further highlighting the newly emerging character of this cluster ( Volkmann et al., 2020 ).…”

Section: Resultsmentioning

confidence: 92%

Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment

Schulte-Schrepping¹,

Reusch²,

Paclik³

et al. 2020

Cell

1,304

216

1,533

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Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DR hi CD11c hi inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DR lo monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.

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Section: Resultsmentioning

confidence: 92%

Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment

Schulte-Schrepping¹,

Reusch²,

Paclik³

et al. 2020

Cell

1,304

216

1,533

View full text Add to dashboard Cite

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“…S6G ). However, expression of CD177, CD274 (PD-L1) and zinc finger DHHC domain-containing palmitoyl transferases ZDHHC19, indicative of an immature and suppressive granulocyte phenotype (Volkmann et al, 2020), was specifically observed in patients with severe COVID-19 ( Fig. 6C ).…”

Section: Resultsmentioning

confidence: 99%

Suppressive myeloid cells are a hallmark of severe COVID-19

Schulte-Schrepping

Reusch

Paclik

et al. 2020

Preprint

101

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'Severe Acute Respiratory Syndrome - Coronavirus-2' (SARS-CoV-2) infection causes Coronavirus Disease 2019 (COVID-19), a mild to moderate respiratory tract infection in the majority of patients. A subset of patients, however, progresses to severe disease and respiratory failure with acute respiratory distress syndrome (ARDS). Severe COVID-19 has been associated with increased neutrophil counts and dysregulated immune responses. The mechanisms of protective immunity in mild forms and the pathogenesis of dysregulated inflammation in severe courses of COVID-19 remain largely unclear. Here, we combined two single-cell RNA-sequencing technologies and single-cell proteomics in whole blood and peripheral blood mononuclear cells (PBMC) to determine changes in immune cell composition and activation in two independent dual-center patient cohorts (n=46 + n=54 COVID-19 samples), each with mild and severe cases of COVID-19. We observed a specific increase of HLA-DR high CD11c high inflammatory monocytes that displayed a strong interferon (IFN)-stimulated gene signature in patients with mild COVID-19, which was absent in severe disease. Instead, we found evidence of emergency myelopoiesis, marked by the occurrence of immunosuppressive pre-neutrophils and immature neutrophils and populations of dysfunctional and suppressive mature neutrophils, as well as suppressive HLA-DR low monocytes in severe COVID-19. Our study provides detailed insights into systemic immune response to SARS-CoV-2 infection and it reveals profound alterations in the peripheral myeloid cell compartment associated with severe courses of COVID-19.

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“…4). In IRI or unilateral ureteral obstruction (UUO) mice, G-CSF is upregulated and the number of neutrophils increases in the injured kidney 30 . IL-12 and IL-33 work together as a stimulant to invariant natural killer T cells in the kidney and promote neutrophils and monocytes/macrophage infiltration into the organ 31 .…”

Section: Discussionmentioning

confidence: 99%

Vagus nerve stimulation even after injury ameliorates cisplatin-induced nephropathy via reducing macrophage infiltration

Uni

Inoue

Nakamura

et al. 2020

Sci Rep

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The efficacy of prior activation of an anti-inflammatory pathway called the cholinergic antiinflammatory pathway (CAP) through vagus nerve stimulation (VNS) has been reported in renal ischemia-reperfusion injury models. However, there have been no reports that have demonstrated the effectiveness of VNS after injury. We investigated the renoprotective effect of VNS in a cisplatin-induced nephropathy model. C57BL/6 mice were injected with cisplatin, and VNS was conducted 24 hours later. Kidney function, histology, and a kidney injury marker (Kim-1) were evaluated 72 hours after cisplatin administration. To further explore the role of the spleen and splenic macrophages, key players in the CAP, splenectomy, and adoptive transfer of macrophages treated with the selective α7 nicotinic acetylcholine receptor agonist GTS-21 were conducted. VNS treatment significantly suppressed cisplatin-induced kidney injury. This effect was abolished by splenectomy, while adoptive transfer of GTS-21-treated macrophages improved renal outcomes. VNS also reduced the expression of cytokines and chemokines, including CCL2, which is a potent chemokine attracting monocytes/macrophages, accompanied by a decline in the number of infiltrating macrophages. Taken together, stimulation of the cAp protected the kidney even after injury in a cisplatin-induced nephropathy model. considering the feasibility and anti-inflammatory effects of VNS, the findings suggest that VNS may be a promising therapeutic tool for acute kidney injury. Despite the advancements in modern medical technology, acute kidney injury (AKI) is still one of the major comorbidities in hospital settings. It is estimated that AKI occurs in approximately 15% of hospitalized patients and 60% of critically ill patients 1 , and morbidity and mortality rates remain high 2,3. In addition, AKI is a risk factor for chronic kidney disease (CKD) and end-stage renal disease (ESRD) 4. Therefore, prevention of AKI development and progression to CKD is essential. Inflammation plays an important role in the pathogenesis of AKI 5. Moreover, chronic inflammation contributes to the progression of CKD. Therefore, suppression of inflammation plays a potential role in treating kidney injury. Recently, a new anti-inflammatory pathway called the cholinergic anti-inflammatory pathway (CAP) has been discovered 6. The CAP consists of both afferent and efferent arms, and both afferent and efferent vagus nerves play important roles. The afferent vagus nerve conducts inflammatory information from the peripheral organs to the central nervous system. In the brainstem, the afferent vagus nerve activates the C1 neurons, which make a major contribution to the central regulation of autonomic function 7 , and further stimulate the efferent vagus nerve 8. Previously, Inoue and Abe et al. reported that vagus nerve stimulation (VNS) protected the kidney from ischemia-reperfusion injury (IRI) through activation of the CAP 9. Although there are many kinds of inflammatory cells such as B cells, T cells, and dendritic cells ...

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Kidney injury enhances renal G-CSF expression and modulates granulopoiesis and human neutrophil CD177 in vivo

Cited by 12 publications

References 67 publications

Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment

Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment

Suppressive myeloid cells are a hallmark of severe COVID-19

Vagus nerve stimulation even after injury ameliorates cisplatin-induced nephropathy via reducing macrophage infiltration

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