Table 2.
In vitro and in vivo studies on netrin-1 and mechanisms in chronic inflammation.
| Chronic Inflammation | ||||
|---|---|---|---|---|
| Model | Receptor | Netrin-1 Expression | Outcome | Ref. |
| Atherosclerosis | ||||
| Analysis of p.R590L variant of netrin-1 (mutNetrin-1) | UNC5B DCC Neogenin |
Decrease in binding capacity to UNC5B and DCC and an increase in binding capacity to neogenin. Stimulation of monocyte adhesion and expression of IL-6, CCL2, and ICAM-1. Diminishing macrophages and smooth muscle cell migration. |
[97] | |
| Induction of Raw264.7 macrophages with oxLDL | UNC5B | ⇑ | Downregulation of CCR7 expression and inhibition of macrophage migration. | [98] |
| Bone marrow transplantation of Ntn-1−/−-deficient cells in LDLR−/− KO mice on western diet in plaque progression | UNC5B Neogenin |
⇑ | Hematopoetic netrin-1 KO prevents atherosclerosis development by mitigating MØ and VSMC influx and facilitating MØ egress | [99] |
| Monocyte- and macrophage-specific tamoxifen-inducible CX3CR1-driven cre recombinase netrin-1 floxed mice (Ntn1fl/fl Cx3cr1creERT2+) in plaque regression | UNC5B | Reduced plaque size and complexity in aortic wall, inflammation resolution, IL-10 production, and efferocytosis by myeloid Ntn1 deletion. | [100] | |
| Obesity | ||||
| Mouse model of diet-induced obesity | Unc5B | ⇑ in obese, but not lean adipose tissue | Expression of netrin-1 and its receptor are regulated by saturated fatty acid. Macrophages with a reduced migratory capacity. Restored by blocking netrin-1. | [52] |
| Hematopoietic deletion of Ntn1 | ⇓ | Relief of adipose tissue macrophage emigration, reduction of inflammation, and improvement of insulin sensitivity. | [52] | |
| Mouse model with myeloid- specific deletion of netrin-1 (Ntn1fl/fl LysMCre+/−; Ntn1 mac) |
not defined | Ntn1 mac mice: modest decrease in HFD-induced adiposity and adipocyte size. Ntn1 mac macrophages: reduced expression of genes involved in arachidonic acid metabolism and decreases in proinflammatory eicosanoids. Myeloid-specific deletion of netrin-1 caused a decrease of ATMs, particularly the resident macrophage subset. Macrophages reprogram the ATM phenotype, leading to reduced adipose inflammation and improved lipid handling and metabolic function. |
[101] | |
| Diabetes | ||||
| Adipose-derived stem cells modified by netrin-1 gene (NTN-1) in vitro, condition of high glucose | ⇑ | Proliferation, migration, adhesion, and inhibition of the apoptosis of ADSCs. | [102] | |
| Injected adipose-derived stem cells modified by netrin-1 gene (NTN-1) in vivo (sciatic denervated mice with type 2 diabetes mellitus) |
⇑ | Capillaries and endothelium were formed by differentiation of N-ADSCs, higher density of microvessels. Upregulation of AKT/PI3K/eNOS/P-38/NF-κB signaling pathways. | [102] | |
| Exogenous netrin-1 in UNC5B-depleted human renal glomerular endothelial cells (HRGECs) | UNC5B | not defined | Inhibition of cell migration and tubulogenesis. Association with SRC pathway deactivation UNC5B antagonizes netrin-1 and that UNC5B upregulation for the enhancement of angiogenesis. |
[103] |
| Destructive Joint Disease / Osteoarthritis | ||||
| Female mice with or without knockout of netrin-1 or receptor to detect differences in expression and effect on bone structure. | UNC5B | ⇑ | Activation of SHP1, inhibition of multinucleation of osteoclasts and preventing bone erosion in autoimmune arthritis. | [104] |
| Mouse model with implanted ultrahigh-molecular-weight-polyethylene particles (UHMWPE) over the calvaria and weekly injection of antibodies for netrin-1 and its receptor | UNC5B | not defined | Reduced particle-induced bone pitting, inflammatory processes, and TRAP (tartrate-resistant acid phosphatase)-positive osteoclasts. | [105] |
| RAW 264.7 mouse monocyte macrophages and air pouch model of bone resorption |
UNC5B | not defined | Effect of netrin-1 via the ERK1/2 signaling pathway on osteoclast development by promoting autophagy. | [106] |