Limits...
Inhibition of lysophosphatidic acid receptors 1 and 3 attenuates atherosclerosis development in LDL-receptor deficient mice

View Article: PubMed Central - PubMed

ABSTRACT

Lysophosphatidic acid (LPA) is a natural lysophospholipid present at high concentrations within lipid-rich atherosclerotic plaques. Upon local accumulation in the damaged vessels, LPA can act as a potent activator for various types of immune cells through its specific membrane receptors LPA1/3. LPA elicits chemotactic, pro-inflammatory and apoptotic effects that lead to atherosclerotic plaque progression. In this study we aimed to inhibit LPA signaling by means of LPA1/3 antagonism using the small molecule Ki16425. We show that LPA1/3 inhibition significantly impaired atherosclerosis progression. Treatment with Ki16425 also resulted in reduced CCL2 production and secretion, which led to less monocyte and neutrophil infiltration. Furthermore, we provide evidence that LPA1/3 blockade enhanced the percentage of non-inflammatory, Ly6Clow monocytes and CD4+ CD25+ FoxP3+ T-regulatory cells. Finally, we demonstrate that LPA1/3 antagonism mildly reduced plasma LDL cholesterol levels. Therefore, pharmacological inhibition of LPA1/3 receptors may prove a promising approach to diminish atherosclerosis development.

No MeSH data available.


Related in: MedlinePlus

Systemic treatment with Ki16425 for 6 weeks reduces CD4+ T-cells in the blood and spleen, with a potency to increase anti-inflammatory TREG cells.(a) Upon 6 weeks of treatment, LPA1/3 antagonism reduced the percentage of CD4+ T-cells in the blood of LPA1/3 blocked mice, as compared to the control. (b) Anti-inflammatory CD4+ TREG and (c) inducible FoxP3+ Helios− TREG cells were detected at higher levels in contrast to (d) lower inflammatory TH1 cells in the blood of the Ki16425 treated mice. (e) In the spleen of Ki16425 treated animals CD4+ T-cells appeared significantly lower. (f) No difference was observed within the overall CD4+ TREG cells. (g) The inducible TREG cells were found substantially decreased. (h) No significant difference was detected in the CD4+ TH1 population. All values are calculated as mean ± SEM. (n = 12/grp, *P < 0.05,**P < 0.01, ****P < 0.0001).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5121611&req=5

f5: Systemic treatment with Ki16425 for 6 weeks reduces CD4+ T-cells in the blood and spleen, with a potency to increase anti-inflammatory TREG cells.(a) Upon 6 weeks of treatment, LPA1/3 antagonism reduced the percentage of CD4+ T-cells in the blood of LPA1/3 blocked mice, as compared to the control. (b) Anti-inflammatory CD4+ TREG and (c) inducible FoxP3+ Helios− TREG cells were detected at higher levels in contrast to (d) lower inflammatory TH1 cells in the blood of the Ki16425 treated mice. (e) In the spleen of Ki16425 treated animals CD4+ T-cells appeared significantly lower. (f) No difference was observed within the overall CD4+ TREG cells. (g) The inducible TREG cells were found substantially decreased. (h) No significant difference was detected in the CD4+ TH1 population. All values are calculated as mean ± SEM. (n = 12/grp, *P < 0.05,**P < 0.01, ****P < 0.0001).

Mentions: Flow cytometric analysis of the white blood cell population showed a significant reduction in the circulating CD4+ T-cell percentage after LPA1/3 inhibition (Fig. 5a, P = 0.036). However, within the CD4+ T-cell population, anti-inflammatory FoxP3+/CD25+/CD4+ TREG percentage was found significantly increased (Fig. 5b, Ki16425: 10.24 ± 0.71% versus control: 7.06 ± 0.41%, P = 0.0013). Among the CD4+ TREG population, FoxP3+ Helios−/CD25+ cells, defined as inducible (i) TREG and generated in secondary lymphoid organs3738, increased significantly in the Ki16425-treated group (Fig. 5c, P = 0.038). The percentage of pro-inflammatory CD4+ TH1 cells in the blood was reduced upon LPA1/3 inhibition (Fig. 5d, P = 0.011). Also in the spleen, CD4+ T-cells were reduced in the Ki16425 treated mice (Fig. 5e, P < 0.0001), with no difference observed however in the overall FoxP3+/CD25+/CD4+ TREG population (Fig. 5f, P = 0.39). Nonetheless, LPA1/3 inhibition resulted in a significant reduction in the inducible CD4+ TREG cells (Fig. 5g, P = 0.025). No significant differences in TH1 cells were observed in this compartment (Fig. 5h, P = 0.09).


Inhibition of lysophosphatidic acid receptors 1 and 3 attenuates atherosclerosis development in LDL-receptor deficient mice
Systemic treatment with Ki16425 for 6 weeks reduces CD4+ T-cells in the blood and spleen, with a potency to increase anti-inflammatory TREG cells.(a) Upon 6 weeks of treatment, LPA1/3 antagonism reduced the percentage of CD4+ T-cells in the blood of LPA1/3 blocked mice, as compared to the control. (b) Anti-inflammatory CD4+ TREG and (c) inducible FoxP3+ Helios− TREG cells were detected at higher levels in contrast to (d) lower inflammatory TH1 cells in the blood of the Ki16425 treated mice. (e) In the spleen of Ki16425 treated animals CD4+ T-cells appeared significantly lower. (f) No difference was observed within the overall CD4+ TREG cells. (g) The inducible TREG cells were found substantially decreased. (h) No significant difference was detected in the CD4+ TH1 population. All values are calculated as mean ± SEM. (n = 12/grp, *P < 0.05,**P < 0.01, ****P < 0.0001).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121611&req=5

f5: Systemic treatment with Ki16425 for 6 weeks reduces CD4+ T-cells in the blood and spleen, with a potency to increase anti-inflammatory TREG cells.(a) Upon 6 weeks of treatment, LPA1/3 antagonism reduced the percentage of CD4+ T-cells in the blood of LPA1/3 blocked mice, as compared to the control. (b) Anti-inflammatory CD4+ TREG and (c) inducible FoxP3+ Helios− TREG cells were detected at higher levels in contrast to (d) lower inflammatory TH1 cells in the blood of the Ki16425 treated mice. (e) In the spleen of Ki16425 treated animals CD4+ T-cells appeared significantly lower. (f) No difference was observed within the overall CD4+ TREG cells. (g) The inducible TREG cells were found substantially decreased. (h) No significant difference was detected in the CD4+ TH1 population. All values are calculated as mean ± SEM. (n = 12/grp, *P < 0.05,**P < 0.01, ****P < 0.0001).
Mentions: Flow cytometric analysis of the white blood cell population showed a significant reduction in the circulating CD4+ T-cell percentage after LPA1/3 inhibition (Fig. 5a, P = 0.036). However, within the CD4+ T-cell population, anti-inflammatory FoxP3+/CD25+/CD4+ TREG percentage was found significantly increased (Fig. 5b, Ki16425: 10.24 ± 0.71% versus control: 7.06 ± 0.41%, P = 0.0013). Among the CD4+ TREG population, FoxP3+ Helios−/CD25+ cells, defined as inducible (i) TREG and generated in secondary lymphoid organs3738, increased significantly in the Ki16425-treated group (Fig. 5c, P = 0.038). The percentage of pro-inflammatory CD4+ TH1 cells in the blood was reduced upon LPA1/3 inhibition (Fig. 5d, P = 0.011). Also in the spleen, CD4+ T-cells were reduced in the Ki16425 treated mice (Fig. 5e, P < 0.0001), with no difference observed however in the overall FoxP3+/CD25+/CD4+ TREG population (Fig. 5f, P = 0.39). Nonetheless, LPA1/3 inhibition resulted in a significant reduction in the inducible CD4+ TREG cells (Fig. 5g, P = 0.025). No significant differences in TH1 cells were observed in this compartment (Fig. 5h, P = 0.09).

View Article: PubMed Central - PubMed

ABSTRACT

Lysophosphatidic acid (LPA) is a natural lysophospholipid present at high concentrations within lipid-rich atherosclerotic plaques. Upon local accumulation in the damaged vessels, LPA can act as a potent activator for various types of immune cells through its specific membrane receptors LPA1/3. LPA elicits chemotactic, pro-inflammatory and apoptotic effects that lead to atherosclerotic plaque progression. In this study we aimed to inhibit LPA signaling by means of LPA1/3 antagonism using the small molecule Ki16425. We show that LPA1/3 inhibition significantly impaired atherosclerosis progression. Treatment with Ki16425 also resulted in reduced CCL2 production and secretion, which led to less monocyte and neutrophil infiltration. Furthermore, we provide evidence that LPA1/3 blockade enhanced the percentage of non-inflammatory, Ly6Clow monocytes and CD4+ CD25+ FoxP3+ T-regulatory cells. Finally, we demonstrate that LPA1/3 antagonism mildly reduced plasma LDL cholesterol levels. Therefore, pharmacological inhibition of LPA1/3 receptors may prove a promising approach to diminish atherosclerosis development.

No MeSH data available.


Related in: MedlinePlus