Transcriptomic Profiling Identifies Neutrophil-Specific Upregulation of Cystatin F as a Marker of Acute Inflammation in Humans

Abstract

Cystatin F encoded by CST7 is a cysteine peptidase inhibitor known to be expressed in natural killer (NK) and CD8+ T cells during steady-state conditions. However, little is known about its expression during inflammatory disease states in humans. We have developed an analytic approach capable of not only identifying previously poorly characterized disease-associated genes but also defining regulatory mechanisms controlling their expression. By exploring multiple cohorts of public transcriptome data comprising 43 individual datasets, we showed that CST7 is upregulated in the blood during a diverse set of infectious and non-infectious inflammatory conditions. Interestingly, this upregulation of CST7 was neutrophil-specific, as its expression was unchanged in NK and CD8+ T cells during sepsis. Further analysis demonstrated that known microbial products or cytokines commonly associated with inflammation failed to increase CST7 expression, suggesting that its expression in neutrophils is induced by an endogenous serum factor commonly present in human inflammatory conditions. Overall, through the identification of CST7 upregulation as a marker of acute inflammation in humans, our study demonstrates the value of publicly available transcriptome data in knowledge generation and potential biomarker discovery.

Identification of key genes related to immune cells in patients with gram-negative sepsis based on weighted gene co-expression network analysis

“…For instance, CST7, CLEC5a, and NEDD4 indirectly interact with NLRC4 and RGL4 in gene networks and are also involved in immune regulation and inflammatory responses. Transcriptomic profiling has verified that neutrophil-specific upregulation of cystatin F (encoded by CST7) is a sign of acute inflammation in humans (46). CST7 is significantly upregulated in patients with sepsis compared to their expression in healthy controls (46)(47)(48).…”

Dissecting the process of human neutrophil lineage determination by using alpha-lipoic acid inducing neutrophil deficiency model

“…Among the four populations, only 75 DEGs were identified. Among DEGs, only granule-related genes and genes highly expressed in neutrophils, including LPO, MPO, LYZ [ 41 ], ELANE, PRTN3, CSTG [ 42 ], CST7 [ 43 ], and CSTA were upregulated by differentiation into neutrophils ( Fig. 3 .…”

“…A). We found that both in vivo- and in vitro- derived neutrophil-biased progenitors highly expressed neutrophil uni-expressed genes or granule-related genes, including MPO, LRG1 [ 45 ], PRTN3, ELANE, CTSG [ 42 ], CST7 [ 43 ], CSTA [ 46 ], and CLEC11A [ 47 ] ( Fig. 4 .…”

Transcriptomic profile investigations highlight a putative role for NUDT16 in sepsis

“…To that point, the growing repertoire of publicly accessible transcriptomic datasets, like those on the Gene Expression Omnibus (GEO), serves as a valuable resource for discovering novel predictors, diagnostic markers and disease progression markers. Diverse reductionist approaches have been used to successfully identify putatively novel genes/functions 5–9 and perform system‐level re‐analyses 10–12 …”