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Microparticles release by adipocytes act as "find-me" signals to promote macrophage migration.

Eguchi A, Mulya A, Lazic M, Radhakrishnan D, Berk MP, Povero D, Gornicka A, Feldstein AE - PLoS ONE (2015)

Bottom Line: The release of MPs was highly regulated and dependent on caspase 3 and Rho-associated kinase.Further analysis identified these MPs as a central chemoattractant in vitro and in vivo.In addition, intravenously transplanting circulating MPs from the ob/ob mice lead to activation of monocytes in circulation and adipose tissue of the wild type mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of California San Diego (UCSD), La Jolla, California, United States of America.

ABSTRACT
Macrophage infiltration of adipose tissue during weight gain is a central event leading to the metabolic complications of obesity. However, what are the mechanisms attracting professional phagocytes to obese adipose tissue remains poorly understood. Here, we demonstrate that adipocyte-derived microparticles (MPs) are critical "find-me" signals for recruitment of monocytes and macrophages. Supernatants from stressed adipocytes stimulated the attraction of monocyte cells and primary macrophages. The activation of caspase 3 was required for release of these signals. Adipocytes exposed to saturated fatty acids showed marked release of MPs into the supernatant while common genetic mouse models of obesity demonstrate high levels of circulating adipocyte-derived MPs. The release of MPs was highly regulated and dependent on caspase 3 and Rho-associated kinase. Further analysis identified these MPs as a central chemoattractant in vitro and in vivo. In addition, intravenously transplanting circulating MPs from the ob/ob mice lead to activation of monocytes in circulation and adipose tissue of the wild type mice. These data identify adipocyte-derived MPs as novel "find me" signals that contributes to macrophage infiltration associated with obesity.

No MeSH data available.


Related in: MedlinePlus

Transplanted circulating MPs from ob/ob mouse lead to monocyte activation in the blood and macrophage infiltration in the adipose tissue.(A) Scheme of transplanted experiment; ob/ob platelet free plasma was collected, circulating MPs were purified and injected into the WT mouse. (B) Dot plot analysis of the entire leukocyte population in blood resulting from the mock, ob ctrl (control) MP, and ob/ob MP injections, respectively. X-axis indicates CD11b intensity and Y-axis indicates Ly6C intensity. (C-D) Flow cytometry analysis of monocyte (CD11b+-Ly6Chigh) percentage (C) and activated monocyte (CD11b+-Ly6Chigh-CD204+) percentage (D) in blood resulting from the mock, ob ctrl MP, or ob/ob MP injections (n = 4 each group). (E) Flow cytometry analysis of infiltrated monocytes (CD11b+-Ly6Chigh) percentage in epididymal (Epi) adipose tissue from the mock, ob ctrl MP, or ob/ob MP injections. P<0.4. Values represent mean ± S.E.M. *P < 0.05; **P < 0.01 compared to ob ctrl MPs as a control.
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pone.0123110.g006: Transplanted circulating MPs from ob/ob mouse lead to monocyte activation in the blood and macrophage infiltration in the adipose tissue.(A) Scheme of transplanted experiment; ob/ob platelet free plasma was collected, circulating MPs were purified and injected into the WT mouse. (B) Dot plot analysis of the entire leukocyte population in blood resulting from the mock, ob ctrl (control) MP, and ob/ob MP injections, respectively. X-axis indicates CD11b intensity and Y-axis indicates Ly6C intensity. (C-D) Flow cytometry analysis of monocyte (CD11b+-Ly6Chigh) percentage (C) and activated monocyte (CD11b+-Ly6Chigh-CD204+) percentage (D) in blood resulting from the mock, ob ctrl MP, or ob/ob MP injections (n = 4 each group). (E) Flow cytometry analysis of infiltrated monocytes (CD11b+-Ly6Chigh) percentage in epididymal (Epi) adipose tissue from the mock, ob ctrl MP, or ob/ob MP injections. P<0.4. Values represent mean ± S.E.M. *P < 0.05; **P < 0.01 compared to ob ctrl MPs as a control.

Mentions: Since we observed increased number of circulating MPs in obese mice (Fig 5A), we examined whether circulating MPs from the plasma of ob/ob mice induce chemotactic activity, such as acute inflammation and stimulation of monocyte infiltration into the adipose tissue of WT mouse. The MPs from plasma of ob/ob (ob/ob-derived MPs) or MPs from plasma of ob ctrl mice (ob ctrl-derived MPs) were purified with sucrose gradient by ultracentrifugation and injected into WT mouse (100 μg/mouse) by intravenous injection (Fig 6A). Accumulation of Inflammatory monocytes (CD11b+-Ly6Chigh) in the blood was three-fold higher in mice injected with ob/ob-derived MPs compared with ob ctrl-derived MPs at 6 h post injection (Fig 6B and 6C). Furthermore, there was also a three-fold increase in activated CD204+ (class A scavenger receptor Type I and II) monocytes in mice injected with ob/ob-derived MPs (Fig 6D). Notably, the number of infiltrated inflammatory macrophages (CD11b+-Ly6Chigh) to epididymal adipose tissue was also increased in the mice injected with ob/ob-derived MPs compared to ob ctrl-derived MPs (Fig 6E). These results suggest that circulating MPs in obese (ob/ob) mice have chemotactic activities for monocyte activation and infiltration to the adipose tissue.


Microparticles release by adipocytes act as "find-me" signals to promote macrophage migration.

Eguchi A, Mulya A, Lazic M, Radhakrishnan D, Berk MP, Povero D, Gornicka A, Feldstein AE - PLoS ONE (2015)

Transplanted circulating MPs from ob/ob mouse lead to monocyte activation in the blood and macrophage infiltration in the adipose tissue.(A) Scheme of transplanted experiment; ob/ob platelet free plasma was collected, circulating MPs were purified and injected into the WT mouse. (B) Dot plot analysis of the entire leukocyte population in blood resulting from the mock, ob ctrl (control) MP, and ob/ob MP injections, respectively. X-axis indicates CD11b intensity and Y-axis indicates Ly6C intensity. (C-D) Flow cytometry analysis of monocyte (CD11b+-Ly6Chigh) percentage (C) and activated monocyte (CD11b+-Ly6Chigh-CD204+) percentage (D) in blood resulting from the mock, ob ctrl MP, or ob/ob MP injections (n = 4 each group). (E) Flow cytometry analysis of infiltrated monocytes (CD11b+-Ly6Chigh) percentage in epididymal (Epi) adipose tissue from the mock, ob ctrl MP, or ob/ob MP injections. P<0.4. Values represent mean ± S.E.M. *P < 0.05; **P < 0.01 compared to ob ctrl MPs as a control.
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pone.0123110.g006: Transplanted circulating MPs from ob/ob mouse lead to monocyte activation in the blood and macrophage infiltration in the adipose tissue.(A) Scheme of transplanted experiment; ob/ob platelet free plasma was collected, circulating MPs were purified and injected into the WT mouse. (B) Dot plot analysis of the entire leukocyte population in blood resulting from the mock, ob ctrl (control) MP, and ob/ob MP injections, respectively. X-axis indicates CD11b intensity and Y-axis indicates Ly6C intensity. (C-D) Flow cytometry analysis of monocyte (CD11b+-Ly6Chigh) percentage (C) and activated monocyte (CD11b+-Ly6Chigh-CD204+) percentage (D) in blood resulting from the mock, ob ctrl MP, or ob/ob MP injections (n = 4 each group). (E) Flow cytometry analysis of infiltrated monocytes (CD11b+-Ly6Chigh) percentage in epididymal (Epi) adipose tissue from the mock, ob ctrl MP, or ob/ob MP injections. P<0.4. Values represent mean ± S.E.M. *P < 0.05; **P < 0.01 compared to ob ctrl MPs as a control.
Mentions: Since we observed increased number of circulating MPs in obese mice (Fig 5A), we examined whether circulating MPs from the plasma of ob/ob mice induce chemotactic activity, such as acute inflammation and stimulation of monocyte infiltration into the adipose tissue of WT mouse. The MPs from plasma of ob/ob (ob/ob-derived MPs) or MPs from plasma of ob ctrl mice (ob ctrl-derived MPs) were purified with sucrose gradient by ultracentrifugation and injected into WT mouse (100 μg/mouse) by intravenous injection (Fig 6A). Accumulation of Inflammatory monocytes (CD11b+-Ly6Chigh) in the blood was three-fold higher in mice injected with ob/ob-derived MPs compared with ob ctrl-derived MPs at 6 h post injection (Fig 6B and 6C). Furthermore, there was also a three-fold increase in activated CD204+ (class A scavenger receptor Type I and II) monocytes in mice injected with ob/ob-derived MPs (Fig 6D). Notably, the number of infiltrated inflammatory macrophages (CD11b+-Ly6Chigh) to epididymal adipose tissue was also increased in the mice injected with ob/ob-derived MPs compared to ob ctrl-derived MPs (Fig 6E). These results suggest that circulating MPs in obese (ob/ob) mice have chemotactic activities for monocyte activation and infiltration to the adipose tissue.

Bottom Line: The release of MPs was highly regulated and dependent on caspase 3 and Rho-associated kinase.Further analysis identified these MPs as a central chemoattractant in vitro and in vivo.In addition, intravenously transplanting circulating MPs from the ob/ob mice lead to activation of monocytes in circulation and adipose tissue of the wild type mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of California San Diego (UCSD), La Jolla, California, United States of America.

ABSTRACT
Macrophage infiltration of adipose tissue during weight gain is a central event leading to the metabolic complications of obesity. However, what are the mechanisms attracting professional phagocytes to obese adipose tissue remains poorly understood. Here, we demonstrate that adipocyte-derived microparticles (MPs) are critical "find-me" signals for recruitment of monocytes and macrophages. Supernatants from stressed adipocytes stimulated the attraction of monocyte cells and primary macrophages. The activation of caspase 3 was required for release of these signals. Adipocytes exposed to saturated fatty acids showed marked release of MPs into the supernatant while common genetic mouse models of obesity demonstrate high levels of circulating adipocyte-derived MPs. The release of MPs was highly regulated and dependent on caspase 3 and Rho-associated kinase. Further analysis identified these MPs as a central chemoattractant in vitro and in vivo. In addition, intravenously transplanting circulating MPs from the ob/ob mice lead to activation of monocytes in circulation and adipose tissue of the wild type mice. These data identify adipocyte-derived MPs as novel "find me" signals that contributes to macrophage infiltration associated with obesity.

No MeSH data available.


Related in: MedlinePlus