TABLE 3.

Effects of modulating innate immunity pathways in experimental DW.

Innate immune pathway	Knockout mice models	Intervention (agent)	Mechanism
TLR signaling	TLR2−/−	—	TLR2/6-MyD88-NF-κb↓
			IL- 1β, TNF-α↓
			DW Healing ↑ Dasu et al. (2010)
	TLR4−/−	—	TLR4-NF-κb↓
			IL-6, TNF-α↓
			DW Healing ↑ Dasu and Jialal, (2013)
	Leprdb/db	nAChR agonists (nicotine).	TLR2-NF-κb↓
			AMP, IL-6↓
			DW Healing ↑ Kishibe et al. (2018)
	TLR3−/−	REG3A	IL-33, REG3A/ RegIIIγ ↑ TLR3–JNK2 ↓ IL-6, TNF-α↓
	JNK2−/−	SHP-1 inhibitor (SSG).	DW Healing ↑ Wu et al. (2016)
	Mll1f/fLyz2Cre+	TLR4 inhibition	MLL1-mediated H3K4me3 ↑ TLR4-MyD88↓
	TLR4−/−	(TAK-242).	DW Healing↑Davis et al. (2020)
NLRP3 inflammasome	Leprdb/db Bitto et al. (2014)	HSWang et al. (2018)	NLRP3 inflammasome-caspase-1-il-1β/il-18 axis↓
		I-κb kinase-β inhibitor (BAY 11–7,082).	IL-1β, IL-18↓
		Purinergic P2X7 receptor inhibitor (brilliant blue G).	DW Healing ↑ Bitto et al. (2014)
	—	PPARα agonists (Fenofibrate).	ROS/TXNIP-NLRP3 inflammasome-caspase-1-il-1β/il-18 axis↓
			DW Healing ↑ Deng et al. (2017)
	—	NLRP3 inhibitor (MCC950).	TLR-4/TLR-9-NF-κb↓
		TLR-4 inhibitor (CLI-095).	ROS/TXNIP-NLRP3 inflammasome-caspase-1-il-1β/il-18 axis↓
		TLR-9 inhibitor (ODN 2088).	IL-1β, IL-18↓
		ROS inhibitor (NAC, dnase I).	DW Healing ↑ Liu et al. (2019)
	Leprdb/db	ROS inhibitor (NAC, dnase I).	NLRP3 inflammasome-caspase-1-il-1β/il-18 axis↓ IL-1β, IL-18↓
		IL-1β blocking antibody (IL-1R1).	DW Healing ↑ Mirza et al. (2014)
		Glyburide caspase-1 inhibitor (YVAD).
cGAS-STING signaling	STING−/-	—	Mitochondrial damage-cGAS-STING-IRF3 ↓ ICAM-1↓
			Improve IR, Glucose intolerance Mao et al. (2017)
JAK-STAT signaling	Leprdb/db	—	IL-12-Stat4↑
			CCL2-CCR2↑
			DW Healing ↓ Cunnion et al. (2017)
	—	—	IL-6 -il-6rα-jak-stat3↑
			SCOS3, DW Healing ↓ Lee et al. (2019)

Partial abbreviation: TLR: Toll-like receptor, STZ: Streptozotocin, NF-κB: Nuclear factor-κB, IL: Interleukin, TNF-α: Tumor necrosis factor-α, nAChRs: Nicotinic acetylcholine receptors, AMP: Adenosine monophosphate, REG3A: Regenerating islet-derived protein 3A, SHP-1: domain-containing protein-tyrosine phosphatase-1, HS: Heparan sulfate, PPARα: Peroxisome proliferator-activated receptors α, EPC: Endothelial progenitor cells, IGF-1: Insulin-like growth factor-1, TGF-β: Transforming growth factor-β, IR: Insulin resistance.