The interferon-gamma pathway is selectively up-regulated in the liver of patients with secondary hemophagocytic lymphohistiocytosis

Abstract

Aim of this study was to investigate the activation of the IFNγ pathway in the affected liver and in the blood of patients with secondary hemophagocytic lymphohistiocytosis (sHLH). To this purpose, the mRNA expression levels of IFNG and IFNγ-inducible genes as well as Tyrosine (701)-phosphorylated signal transducer and activator of transcription 1 (STAT1) protein levels were evaluated in the liver and in peripheral blood mononuclear cells (PBMCs) of three patients with sHLH with predominant liver involvement. The mRNA expression levels of IFNG and IFNγ-inducible genes were markedly higher in patient livers compared to control livers and to one disease control liver. Conversely, slight differences in the expression levels of Type I IFN-inducible genes and other classical inflammatory cytokine genes were found. Further supporting the activation of the IFNγ pathway, higher protein levels of phosphorylated and total STAT1 were detected in patient livers compared to control livers. When the expression of the same genes analysed in liver tissues was evaluated in PBMCs collected from 2 out of 3 patients before the liver biopsy, we found that mRNA levels of IFNγ-inducible genes were markedly increased. Accordingly, high circulating levels of IFNγ-inducible CXCL9 were observed in patients. Altogether, these data demonstrate the selective and marked up-regulation of the IFNγ pathway in the liver tissue and blood of patients with active sHLH. Finally, we show that measurement of circulating CXCL9 levels and evaluation of IFNγ–inducible gene expression levels in PBMCs may represent a new valid tool to better identify patients with suspected HLH with predominant liver involvement.

Monocytes From Patients With Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis Are Hyperresponsive to Interferon Gamma

“…In addition, we found a statistically significant correlation of total STAT1 levels with pSTAT1 levels in sHLH/MAS patients. These data are consistent with previous findings demonstrating that STAT1 and pSTAT1 levels are strongly increased in target tissues, such as liver and lung, of patients and animals with sHLH/MAS ( 5 , 8 , 9 ).…”

“…Indeed, addition of dexamethasone to PBMC cultures has been demonstrated to result in the suppression of STAT1 expression and, therefore, in a dramatic inhibition of IFNγ signaling pathway activation, as revealed by suppression of IFNγ-inducible gene expression ( 22 ). Our observation also confirms our previous findings in PBMCs collected from one patient with sHLH: total STAT1 and pSTAT1 levels were significantly increased during the acute phase of the disease, but they underwent a marked decrease following initiation of treatment with glucocorticoids ( 9 ). Glucocorticoids are often used in the early phase of the disease to stabilize patients with rapidly progressive worsening disease.…”

“…Based on several data demonstrating that, in vivo and ex vivo , glucocorticoids inhibits IFNγ-mediated phosphorylation of STAT1 ( 9 , 22 ), we divided sHLH/MAS patients into two groups: patients without any treatment at time of blood sampling (untreated patients, n=10) and patients who were already receiving glucocorticoids (treated patients, n=14). We found that untreated sHLH/MAS patients showed significantly higher basal pSTAT1 levels in monocytes compared to treated sHLH/MAS patients, as well as to all the other disease control groups ( Figure 1B ).…”

The Prognosis Role of AST/ALT (De Ritis) Ratio in Patients with Adult Secondary Hemophagocytic Lymphohistiocytosis

“…One possible speculation is that periportal lymphocytic infiltration could aberrantly damage liver cells and promote further mitochondrial dysfunction, resulting in the accumulation of serum transaminase [ 23 , 24 ]. In addition, IFN- γ has been proven to be a key cytokine that drives disease development in sHLH [ 25 ], stimulates hepatic inflammation by increasing TNF and IL-6, and induces hepatocyte apoptosis via a BCL2-mediated pathway [ 26 ]. Moreover, an elevated level of AST compared with ALT is hypothesized to be associated with increased cancer cell high proliferative status and normal tissue damage and can result in the higher activation of circulating AST [ 4 ], in line with a large part of the distribution in our 165 patients with MHLH.…”

Proceedings from the 2nd Next Gen Therapies for Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome symposium held on October 3-4, 2019

“…Type I IFN induced gene expression was also roughly normal. These observations suggest that IFN-γ and IFN-induced pathways might be an attractive therapeutic target in this patient population as well [36].…”