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Review
. 2023 Jan 24:14:1077041.
doi: 10.3389/fimmu.2023.1077041. eCollection 2023.

PADs and NETs in digestive system: From physiology to pathology

Yi-Hang Song  1 , Zhi-Jie Wang  1 , Le Kang  1 , Zi-Xuan He  1 , Sheng-Bing Zhao  1 , Xue Fang  1 , Zhao-Shen Li  1 , Shu-Ling Wang  1 , Yu Bai  1
Affiliations
Review

PADs and NETs in digestive system: From physiology to pathology

Yi-Hang Song et al. Front Immunol. .

Abstract

Peptidylarginine deiminases (PADs) are the only enzyme class known to deiminate arginine residues into citrulline in proteins, a process known as citrullination. This is an important post-translational modification that functions in several physiological and pathological processes. Neutrophil extracellular traps (NETs) are generated by NETosis, a novel cell death in neutrophils and a double-edged sword in inflammation. Excessive activation of PADs and NETs is critically implicated in their transformation from a physiological to a pathological state. Herein, we review the physiological and pathological functions of PADs and NETs, in particular, the involvement of PAD2 and PAD4 in the digestive system, from inflammatory to oncological diseases, along with related therapeutic prospects.

Keywords: cancer; citrullination; digestive system; inflammation; peptidylarginine deiminase.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The process of citrullination mediated by PAD. (A) Protein citrullination mediated by PADs. (B) Primary substrates, distribution, and physiological functions of PADs.
Figure 2
Figure 2
Gene expression of PADI1~PADI4 in different human tissues. Gene expression data is provided by ARCHS4 database (6) (https://maayanlab.cloud/archs4/index.html).
Figure 3
Figure 3
Pathological Roles of PAD2/4 in digestive diseases. (A) PAD4-mediated histone citrullination results in NETs and contributes to various inflammatory and oncological diseases in the digestive system. (B) Citrullination of extracellular non-histone proteins mediated by PAD4 promotes liver metastasis in colorectal cancer. (C) PAD2 promotes colorectal cancer cell invasion and liver metastasis by METs and citrullination of β-catenin. (D) PAD2 is highly expressed in several pancreatic cancer cells, and selective inhibitors suppress the invasion and regulate the secretion of anti- or pro-oncogenic miRNA in extracellular vesicles. (E) PAD2 inhibition hinders cell growth and migration in gastric cancer. (F) PAD2 is elevated in septic AP and correlates with CitH3 and patient prognosis.
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