Necroptosis in inflammatory bowel disease and other intestinal diseases

Table 1 Effects of necroptosis in intestinal diseases

Disease	Expression of necroptosis moleculars	Pathological processes may involve after the activation of Necroptosis
IBD	RIPK3 upregulated MLKL upregulated, caspase-8 downregulated	(1) Impair intestinal epithelial barrier and membrane permeability
		(2) Commensal bacteria invade the mucosa through TLR signaling
		(3) Reduce number of Paneth cell
		(4) Increase expression of cytokines (e.g., IL-8, IL-1β, IL-33, HMGB1)
		(5) Translocation of NF-κB p65 and assembly of inflammasomes NALRP3
CRC	RIPK3 downregulated,	(1) Suppress excessive activation of NF-κB, STAT3, AKT and Wnt-β–catenin pathways
	RIPK1 downregulated	(2) Overcome the apoptosis tolerance in CRC and suppress tumor growth and metastasis
Intestinal infectious diseases	RIPK3 and MLKL upregulated when caspase-8 is deficient	(1) Impair the integrity of intestinal epithelial barrier
		(2) Increase levels of cytokines and chemokines, and decrease levels of mucus and mucin-2
		(3) TLR-3 mediate necroptosis through TRIF and TLR-4 mediates necroptosis through TNF-α

IBD: Inflammatory bowel disease; CRC: Colorectal cancer; RIPK: Receptor interacting protein kinase; IL: Interleukin; MLKL: Mixed lineage kinase like protein; TLR: Toll-like receptor; TNF: Tumor necrosis factor; STAT: Signal transducer and activator of transcription.