Insights into the pathogenic roles and targeted therapy of neutrophil extracellular traps in inflammatory bowel disease

Table 2 Therapeutic targets: Inhibition of neutrophil extracellular traps to ameliorate progression of inflammatory bowel disease

Agent	Target molecule/function	Effect	Disease/animal model	Ref.
Cl-amidine	PAD inhibitor	Inhibit colon inflammation; stimulate apoptosis of inflammatory cells in vitro and in vivo	DSS-induced mouse model	Chumanevich et al[66]
Butyrate	Suppresses neutrophil migration and NETs production	Ameliorate mucosal inflammation	DSS-induced murine colitis	Li et al[69]
Cyclosporine A	Inhibit NETs via the regulating PPP	Reduce ROS-dependent NETs release via downregulating PPP and cellular ROS levels by decreasing G6PD activity directly by activating the P53 protein	DSS-induced colitis mouse model	Xu et al[70]
Hydroxychloroquine	Inhibit NET formation	HCQ inhibit the activation of MEK/ERK/ROS signaling pathway	DSS induced colitis	Jiang and Zhang[74]
Thymopentin	Inhibit NET formation	Reduced DAI, weight loss and colon shrinkage; decreased MPO, NE, citH3, PAD4, dsDNA	TNBS-induced colitis mouse model	Cao et al[79]
PAD4 genetic deficiency	Down-regulate cGAS-STING pathway	Inhibit NET formation, protect the intestinal barrier, alleviate intestinal inflammation	DSS-induced colitis mice	Sun et al[46]
CXCR1 and CXCR2	Promote UC and NET formation through neutrophil chemotaxis and PAD4-mediated pathways	Higher expression of CXCR1/CXCR2 in colon tissues of UC patients	UC; summary data from a genome-wide association study and FinnGen	Xv et al[71]
Hydrogen sulfide	Inhibit NET formation	Inhibit the expression of NF-κB and HMGB1; elevate the expression of anti-inflammatory mediator UCHL-1	TNBS-induced colitis rat model	Török et al[80]

PAD4: Peptidylarginine deiminase 4; NETs: Neutrophil extracellular traps; PPP: Pentose phosphate pathway; cGAS: Cyclic guanosine monophosphate-adenosine monophosphate synthase; STING: Stimulator of interferon genes; UC: Ulcerative colitis; ROS: Reactive oxygen species; G6PD: Glucose-6-phosphate dehydrogenase; HCQ: Hydroxychloroquine; ERK: Extracellular regulated protein kinases; MEK: Mitogen-activated protein kinase kinase; DAI: Disease activity index; MPO: Myeloperoxidase; NE: Neutrophil elastase; citH3: Citrullinated histone H3; dsDNA: Double-stranded DNA; NF-κB: Nuclear factor kappa-B; HMGB1: High-mobility group box 1; TNBS: 2,4,6-trinitrobenzene sulfonic acid; DSS: Dextran sulfate sodium.