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Triglyceride-Rich Lipoproteins Modulate the Distribution and Extravasation of Ly6C/Gr1(low) Monocytes.

Saja MF, Baudino L, Jackson WD, Cook HT, Malik TH, Fossati-Jimack L, Ruseva M, Pickering MC, Woollard KJ, Botto M - Cell Rep (2015)

Bottom Line: We observed an increased crawling and retention of the Gr1(low) monocytes at the endothelial interface and a marked accumulation of CD68(+) macrophages in several organs.Hypertriglyceridemia was accompanied by an increased expression of tissue, and plasma CCL4 and blood Gr1(low) monocyte depletion involved a pertussis-toxin-sensitive receptor axis.The behavior of these cells in response to dyslipidemia highlights the significant impact that high levels of triglyceride-rich lipoproteins may have on innate immune cells.

View Article: PubMed Central - PubMed

Affiliation: Centre for Complement and Inflammation Research, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, Du Cane Road, London W12 ONN, UK.

No MeSH data available.


Related in: MedlinePlus

In Vivo Behavior of CX3CR1high Monocytes under P-407-Induced DyslipidemiaCx3cr1gfp/+ mice were treated with PBS or P-407 for 7 days and ear dermis vasculature imaged by intravital microscopy.(A) Examples of intravascular crawling cells (blue arrow) or tissue cells (white arrow) with PBS or P-407 treatment. Scale bars, 50 μm.(B) Quantitative representation of the number of intravascular crawling cells per hour, crawling velocity and track displacement after each treatment. n = 3 per group. ∗∗∗p < 0.001 from PBS control. ns, nonsignificant. Scale bars, 50 μm.(C) Same as (A) and (B) except that representative mesentery vasculature from Cx3cr1gfp/gfp or Cx3cr1gfp/+ mice were imaged over 60 min. Region of interest (ROI) was selected which demonstrates gallery over time of CX3CR1high cell accumulation at the endothelial interface (dotted line) following P-407 treatment. Representative of four mice; ∗∗p < 0.01. Scale bar, 50 μm.(D and E) As in (C), where (D) shows examples of tissue from an ROI (500 μm2) away from the venule showing accumulation of tissue GFP+ cells after P-407 treatment. Two mice representative of four. Scale bar, 100 μm. (E) Quantitative representation of the number of tissue GFP+ cells in PBS- and P-407-treated Cx3cr1gfp/gfp or Cx3cr1gfp/+ mice. n = 3 per group. ∗p < 0.05 and ∗∗p < 0.01.See also Figure S4.
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fig3: In Vivo Behavior of CX3CR1high Monocytes under P-407-Induced DyslipidemiaCx3cr1gfp/+ mice were treated with PBS or P-407 for 7 days and ear dermis vasculature imaged by intravital microscopy.(A) Examples of intravascular crawling cells (blue arrow) or tissue cells (white arrow) with PBS or P-407 treatment. Scale bars, 50 μm.(B) Quantitative representation of the number of intravascular crawling cells per hour, crawling velocity and track displacement after each treatment. n = 3 per group. ∗∗∗p < 0.001 from PBS control. ns, nonsignificant. Scale bars, 50 μm.(C) Same as (A) and (B) except that representative mesentery vasculature from Cx3cr1gfp/gfp or Cx3cr1gfp/+ mice were imaged over 60 min. Region of interest (ROI) was selected which demonstrates gallery over time of CX3CR1high cell accumulation at the endothelial interface (dotted line) following P-407 treatment. Representative of four mice; ∗∗p < 0.01. Scale bar, 50 μm.(D and E) As in (C), where (D) shows examples of tissue from an ROI (500 μm2) away from the venule showing accumulation of tissue GFP+ cells after P-407 treatment. Two mice representative of four. Scale bar, 100 μm. (E) Quantitative representation of the number of tissue GFP+ cells in PBS- and P-407-treated Cx3cr1gfp/gfp or Cx3cr1gfp/+ mice. n = 3 per group. ∗p < 0.05 and ∗∗p < 0.01.See also Figure S4.

Mentions: Gr1low monocytes are thought to monitor endothelial integrity (Auffray et al., 2007; Carlin et al., 2013b). To examine the effect of the P-407-induced hyper-TGRL environment on the Gr1low monocytes at the endothelial interface, we used the Cx3cr1gfp reporter mouse strain. This has been widely used to discriminate the two monocyte subpopulations (Geissmann et al., 2003) and enables Gr1lowCX3CR1high monocytes to be tracked in situ by intravital microscopy (Auffray et al., 2007; Cros et al., 2010). Analysis of monocyte behavior in vivo showed that the number of intravascular crawling GFP+ cells per hour in the ear dermis was higher in the mice treated with P-407 for 7 days compared to the PBS counterparts (Figures 3A and 3B; Movies S1 and S2). Analysis of the intravital images revealed an increased accumulation of extravascular GFP+ cells with a migratory behavior in the P-407-treated animals (Figures 3A and S4A). We then performed in situ experiments in the mesentery of Cx3cr1gfp/gfp and Cx3cr1gfp/+ mice (Figures 3C–3E) and found a marked accumulation of GFP+ cells at the endothelial interface over 1 hr in P-407-treated Cx3cr1gfp/+ and Cx3cr1gfp/gfp mice (Figure 3C; Movies S3 and S4). This was accompanied by decreased velocity and track displacement (Figure 3C), both indicators of enhanced dwell time and endothelial retention. In addition, we observed again a significant increase in tissue (extravascular) GFP+ cells with a migratory behavior (Figures 3D, 3E, and S4B). Since there was no difference between Cx3cr1gfp/+ and Cx3cr1gfp/gfp mice, this implies that under our hyper-TGRL conditions, the Gr1low monocytes had acquired the ability to extravasate independently of CX3CL1 signaling.


Triglyceride-Rich Lipoproteins Modulate the Distribution and Extravasation of Ly6C/Gr1(low) Monocytes.

Saja MF, Baudino L, Jackson WD, Cook HT, Malik TH, Fossati-Jimack L, Ruseva M, Pickering MC, Woollard KJ, Botto M - Cell Rep (2015)

In Vivo Behavior of CX3CR1high Monocytes under P-407-Induced DyslipidemiaCx3cr1gfp/+ mice were treated with PBS or P-407 for 7 days and ear dermis vasculature imaged by intravital microscopy.(A) Examples of intravascular crawling cells (blue arrow) or tissue cells (white arrow) with PBS or P-407 treatment. Scale bars, 50 μm.(B) Quantitative representation of the number of intravascular crawling cells per hour, crawling velocity and track displacement after each treatment. n = 3 per group. ∗∗∗p < 0.001 from PBS control. ns, nonsignificant. Scale bars, 50 μm.(C) Same as (A) and (B) except that representative mesentery vasculature from Cx3cr1gfp/gfp or Cx3cr1gfp/+ mice were imaged over 60 min. Region of interest (ROI) was selected which demonstrates gallery over time of CX3CR1high cell accumulation at the endothelial interface (dotted line) following P-407 treatment. Representative of four mice; ∗∗p < 0.01. Scale bar, 50 μm.(D and E) As in (C), where (D) shows examples of tissue from an ROI (500 μm2) away from the venule showing accumulation of tissue GFP+ cells after P-407 treatment. Two mice representative of four. Scale bar, 100 μm. (E) Quantitative representation of the number of tissue GFP+ cells in PBS- and P-407-treated Cx3cr1gfp/gfp or Cx3cr1gfp/+ mice. n = 3 per group. ∗p < 0.05 and ∗∗p < 0.01.See also Figure S4.
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fig3: In Vivo Behavior of CX3CR1high Monocytes under P-407-Induced DyslipidemiaCx3cr1gfp/+ mice were treated with PBS or P-407 for 7 days and ear dermis vasculature imaged by intravital microscopy.(A) Examples of intravascular crawling cells (blue arrow) or tissue cells (white arrow) with PBS or P-407 treatment. Scale bars, 50 μm.(B) Quantitative representation of the number of intravascular crawling cells per hour, crawling velocity and track displacement after each treatment. n = 3 per group. ∗∗∗p < 0.001 from PBS control. ns, nonsignificant. Scale bars, 50 μm.(C) Same as (A) and (B) except that representative mesentery vasculature from Cx3cr1gfp/gfp or Cx3cr1gfp/+ mice were imaged over 60 min. Region of interest (ROI) was selected which demonstrates gallery over time of CX3CR1high cell accumulation at the endothelial interface (dotted line) following P-407 treatment. Representative of four mice; ∗∗p < 0.01. Scale bar, 50 μm.(D and E) As in (C), where (D) shows examples of tissue from an ROI (500 μm2) away from the venule showing accumulation of tissue GFP+ cells after P-407 treatment. Two mice representative of four. Scale bar, 100 μm. (E) Quantitative representation of the number of tissue GFP+ cells in PBS- and P-407-treated Cx3cr1gfp/gfp or Cx3cr1gfp/+ mice. n = 3 per group. ∗p < 0.05 and ∗∗p < 0.01.See also Figure S4.
Mentions: Gr1low monocytes are thought to monitor endothelial integrity (Auffray et al., 2007; Carlin et al., 2013b). To examine the effect of the P-407-induced hyper-TGRL environment on the Gr1low monocytes at the endothelial interface, we used the Cx3cr1gfp reporter mouse strain. This has been widely used to discriminate the two monocyte subpopulations (Geissmann et al., 2003) and enables Gr1lowCX3CR1high monocytes to be tracked in situ by intravital microscopy (Auffray et al., 2007; Cros et al., 2010). Analysis of monocyte behavior in vivo showed that the number of intravascular crawling GFP+ cells per hour in the ear dermis was higher in the mice treated with P-407 for 7 days compared to the PBS counterparts (Figures 3A and 3B; Movies S1 and S2). Analysis of the intravital images revealed an increased accumulation of extravascular GFP+ cells with a migratory behavior in the P-407-treated animals (Figures 3A and S4A). We then performed in situ experiments in the mesentery of Cx3cr1gfp/gfp and Cx3cr1gfp/+ mice (Figures 3C–3E) and found a marked accumulation of GFP+ cells at the endothelial interface over 1 hr in P-407-treated Cx3cr1gfp/+ and Cx3cr1gfp/gfp mice (Figure 3C; Movies S3 and S4). This was accompanied by decreased velocity and track displacement (Figure 3C), both indicators of enhanced dwell time and endothelial retention. In addition, we observed again a significant increase in tissue (extravascular) GFP+ cells with a migratory behavior (Figures 3D, 3E, and S4B). Since there was no difference between Cx3cr1gfp/+ and Cx3cr1gfp/gfp mice, this implies that under our hyper-TGRL conditions, the Gr1low monocytes had acquired the ability to extravasate independently of CX3CL1 signaling.

Bottom Line: We observed an increased crawling and retention of the Gr1(low) monocytes at the endothelial interface and a marked accumulation of CD68(+) macrophages in several organs.Hypertriglyceridemia was accompanied by an increased expression of tissue, and plasma CCL4 and blood Gr1(low) monocyte depletion involved a pertussis-toxin-sensitive receptor axis.The behavior of these cells in response to dyslipidemia highlights the significant impact that high levels of triglyceride-rich lipoproteins may have on innate immune cells.

View Article: PubMed Central - PubMed

Affiliation: Centre for Complement and Inflammation Research, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, Du Cane Road, London W12 ONN, UK.

No MeSH data available.


Related in: MedlinePlus