Table 1 Potential ligands and roles of TLR9 in cardiometabolic disorders

Adipose tissue

DNA fragments

- Induction of insulin resistance

- Induction of adipose tissue inflammation

- HFD feeding

- WT and Tlr9^-/- mice

- TLR9 antagonist

- Murine peritoneal macrophages

- Human study

[10]

Nucleic acids

- Induction of insulin resistance

- Induce adipose tissue and liver inflammation

- HFD feeding

- WT mice

- Inhibitors of ET formation or a TLR7/9 antagonist

[11]

- Up-regulation of inflammatory cytokines and chemokines

- HFD feeding

- ob/ob and WT mice

[12]

- Improvement of insulin resistance*

- Reduction of adipose tissue inflammation*

- HFD feeding

- WT and Tlr9^-/- mice

[13]

Liver

HMGB1

- Increase of body weight gain

- Increase of hepatic inflammation

- HFD feeding

- WT and Tlr9^-/- mice

- Anti-HMGB1 antibody

[14]

mtDNA

- Increase of NAFLD activity

- Induction of liver inflammation

- HFD feeding

- WT, Tlr9^-/-, and macrophage-specific Tlr9-/- mice

- TLR9 antagonist

- Human study

[15]

- Increase of non-apoptotic hepatocyte death

- Promotion of liver fibrosis

- Induction of liver inflammation

- HFD feeding

- Hepatocyte-specific DNase 2a^-/- mice

- TLR9 agonist/antagonist

- Murine hepatocyte cell line

[16]

Not identified

- Stimulation of steatosis, inflammation, and fibrosis

- Induction of insulin resistance

- CDAA diet-feeding

- WT, Tlr9^-/-, Il1r^-/-, and Myd88^-/- mice

- Murine Kupffer cells

[17]

Vasculature

DNA fragments

- Association with coronary artery disease severity

- Human study

[18]

- Promotion of atherosclerotic lesion development

- Apoe^-/- and Tlr9^-/-Apoe^-/- mice

- Angiotensin II infusion

- Murine peritoneal macrophages

- Human study

[19]

- Promotion of atherosclerotic lesion development

- Promotion of inflammatory activation of Endothelial cells

- Promotion of inflammatory activation of T cells and pDCs

- Apoe^-/- mice

- TLR9 agonist

- Peripheral blood mononuclear cells

- Human study

[20]

HMGB1

- Promotion of vascular injury-induced neointima hyperplasia

- Increase of foam cell accumulation

- Promotion of inflammatory activation of macrophages

- WT and Tlr9^-/- mice

- Vascular injury-induced neointima hyperplasia

- HMGB-1 and anti-HMGB1 antibody

- Murine peritoneal macrophages and RAW264.7 cells

[21]

- Promotion of vascular injury-induced neointima hyperplasia

- Increase of foam cell accumulation

- Promotion of inflammatory activation of macrophages

- Apolipoprotein E*3-Leiden mice

- Vascular injury-induced neointima hyperplasia

- TLR7/9 dual antagonist

- Murine BMDMs

[22]

Not identified

- Promotion of inflammatory activation of macrophages

- Promotion of foam cell formation

- Murine peritoneal macrophages and RAW264.7 cells

- TLR9 agonist

[23, 24]

- Promotion of inflammatory activation of pDCs

- Induction of plaque destabilization

- Leukocytes collected from human atherosclerotic lesions

(pDCs and T cells)

- Peripheral blood mononuclear cells

- TLR9 agonist

[25]

- Promotion of atherosclerotic lesion development

- Stimulating endothelial dysfunction

- Promotion of inflammatory cell accumulation

- Apoe^-/- mice and WT mice

- Electric denudation of carotid artery

- TLR9 agonist

[26]

- Inhibition of atherosclerosis development*

- Reduction of vascular inflammation*

- Reduction of T cell accumulation*

- Increase of cholesterol level

- Apoe^-/- and Tlr9^-/-Apoe^-/- mice

- TLR9 agonist

[27]

Heart

mtDNA

- Related with the development of heart failure after TAC

- Worsen survival after TAC

- Cardiomyocyte-specific DNase2a^-/- mice

- TAC

- TLR9 antagonist

- Adult murine cardiomyocytes

[28]

- Induction of cardiomyocyte death

- WT and NF-κB luciferase reporter mice

- Primary cardiac cells and cardiac fibroblasts

- mtDNA and TLR9 agonist

[29]

-Induction of inflammatory cell activation

- Human study

- THP-1 cells, Raji cells, and HUVECs

- mtDNA

- TLR9 antagonist

[30]