- Research article
- Open Access
Macropinocytosis is decreased in diabetic mouse macrophages and is regulated by AMPK
© Guest et al; licensee BioMed Central Ltd. 2008
- Received: 28 April 2008
- Accepted: 30 July 2008
- Published: 30 July 2008
Macrophages (MΦs) utilize macropinocytosis to integrate immune and metabolic signals in order to initiate an effective immune response. Diabetes is characterized by metabolic abnormalities and altered immune function. Here we examine the influence of diabetes on macropinocytosis in primary mouse macrophages and in an in vitro diabetes model.
The data demonstrate that peritoneal MΦs from diabetic (db/db) mice had reduced macropinocytosis when compared to MΦs from non-diabetic (db/+) mice. Additionally, MΦs cultured in hyperglycemic conditions were less adept at macropinocytosis than those cultured in low glucose. Notably, AMP-activated protein kinase (AMPK) activity was decreased in MΦs cultured in hyperglycemic conditions. Activation of AMPK with leptin or 5-aminoimidazole-4-carboxamide-1-β-riboside (AICAR) increased macropinocytosis and inhibition of AMPK with compound C decreased macropinocytosis.
Taken together, these findings indicate that MΦs from diabetic mice have decreased macropinocytosis. This decrease appears dependent on reduced AMPK activity. These results demonstrate a previously unrealized role for AMPK in MΦs and suggest that increasing AMPK activity in diabetic MΦs could improve innate immunity and decrease susceptibility to infection.
- Diabetic Condition
- Uptake Experiment
- Hyperglycemic Condition
- Macrophage Phenotype
- Chronic Insulin Treatment
MΦs are critical mediators of various immune functions. One of the most important actions the MΦ plays is coordinating innate and adaptive immunity. To do this, MΦs must integrate signals from the local microenvironment with signals from the entire organism to assume an appropriate phenotype . One of the ways MΦs do this is through macropinocytosis or 'drinking' large amounts of extracellular fluid. Macropinocytosis is characterized by the uptake of fluid through relatively large vacuoles (up to 5 microns) [2, 3]. This process is similar to phagocytosis in a number of ways including the formation of an actin-rich ruffle with a structure similar to a pseudopodia and PI3-kinase dependent rearrangement of the plasma membrane [2, 3]. However, these processes differ in some ways [2, 3]. One of these differences is that phagocytosis utilizes ligand specific receptors while macropinocytosis is relatively non-specific allowing for a rapid unsaturable sampling of the heterogenous surrounding fluid including nutrients and pathogens. This fluid is concentrated and acidified in lysosomes, which usually destroy any pathogens contained within. The peptides are then processed and, in the case of professional antigen presenting cells, these peptides are shuttled back to the cell membrane in the context of MHC-II and can participate in the activation of T-cells . Thus, macropinocytosis acts as a bridge between innate and adaptive immunity.
In the last decade, our understanding of how metabolism and immunity interact has grown a great deal. These complex systems share numerous components that are critical to ensure the fitness of an organism. One of the best examples of this interdependence is seen in diabetes. Diabetes is characterized by an inability to efficiently utilize glucose. As a result, those with diabetes are plagued by pathological complications including chronic inflammation [5–7] and a susceptibility to infectious pathogens including Staphylococcus aureus, Streptococcus pneumonia and Mycobacterium tuberculosis . Another important modulator that is altered in diabetes is leptin. Leptin is a 16 kDa protein that is primarily secreted by adipose tissue and is structurally similar to the long-chain helical cytokine family including IL-6 . It is recognized as an indicator of whole body energy levels and acts as a regulator of satiety in the hypothalamus . However, studies with mice lacking a functional leptin system display a wide range of defects including impaired wound healing [11, 12], increased uptake of modified LDL  and decreased phagocytosis of Klebsiella pneumoniae  indicating that leptin plays a significant function in immunity. Notably, several studies have shown that leptin activates AMPK in a number of cell types outside the central nervous system [15, 16]. AMPK is well known as a master regulator of intracellular energy status, but recent work has also alluded to a roll as a key regulator of immune cell function including cytokine secretion [17, 18] and chemotaxis . In addition, activation of AMPK has been shown to improve some of the symptoms of diabetes . Given the alterations to the immune system found in diabetes, we wanted to see if MΦs from diabetic mice had decreased macropinocytosis and, if so, determine which factors contributed to this alteration. Importantly, we found that macropinocytosis was decreased in MΦs cultured in hyperglycemic conditions and indicate that this decrease was caused by decreased AMPK activation.
Peritoneal MΦs from diabetic (db/db) mice and MΦs cultured in diabetic conditions have decreased macropinocytosis
Macropinocytosis is the fluid-phase endocytic process decreased in MΦs cultured in diabetic conditions
MΦs cultured in chronic hyperglycemic conditions have decreased macropinocytosis when compared to control cells
AMP-activated protein kinase activity is decreased in MΦs cultured in diabetic conditions and regulates macropinocytosis
MΦs must be capable of adapting to diverse immune and metabolic environments ranging from the hypoxic, nutrient poor surroundings of a necrotic tumor to the well oxygenated nutrient rich environment of the lung. In order to provide the energy necessary to perform their immune functions, MΦs either utilize glycolysis or oxidative phosphorylation. Work by Odegaard et al., shows that this switch is a critical determinant of macrophage phenotype and function . Additionally, they showed that disruption of this phenotypic switch may be an important component of insulin resistance and hyperglycemia.
The mouse macrophage like cell line, RAW 264.7, was purchased from American Type Culture Collection (Rockville, MD). All cell culture reagents and chemicals were purchased from Sigma (St. Louis, MO) except as noted below. FBS (0.05 ng/mL, 0.48 EU/mL endotoxin) and Leptin were purchased from Atlanta Biologicals (Norcross, GA). LY 294002 (Cat# 440202), rottlerin (Cat# 557370), 5-Aminoimidazole-4-carboxamide-1-β-riboside (AICAR) (Cat# 123040), 6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyrrazolo [1,5-a]-pyrimidine (compound C) (Cat# 171260) and bisindolylmaleimide (Cat# 203293) were purchased from Calbiochem (La Jolla, CA). Propidium iodide was purchased from Molecular Probes (Eugene, OR). Anti-AMPKα 1/2 (Cat# sc-25792), anti-phoso AMPK (Threonine 172) (Cat# sc-33524-R) and Culture Micro Slides (sc-24978) were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Fluormount G was purchased from Southern Biotechnology.
All animal care and use was conducted in accordance with the Guide for the Care and Use of Laboratory Animals (NRC). 8- to 12-week-old B6.Cg-M+/+Leprdb (db/+) and B6.Cg-+Leprdb/+Leprdb (db/db) were bred in house from mice purchased from The Jackson Laboratories (Bar Harbor, Maine). Mice were housed in standard shoebox cages and allowed pelleted food (NIH 5K52; LabDiet, Purina Mills Inc., Brentwood, MO) and water ad libitum in a temperature (72°C) and humidity (45–55%) controlled environment with a 12/12-h dark-light cycle (7:00 a.m. – 7:00 p.m.).
Peritoneal Macrophage Isolation
Mice were sacrificed by CO2 asphyxiation and peritoneal fluid was collected by lavaging the peritoneum twice with 5 ml ice cold low glucose growth media (glucose-free RPMI 1640 media supplemented with 10% FBS, 1 g/L glucose, 2 g/L sodium bicarbonate, 110 mg/L sodium pyruvate, 62.1 mg/L penicillin and 100 mg/L streptomycin, 10 mM HEPES pH 7.4), followed immediately by analysis or use in ex vivo experiments. For ex vivo experiments, cells were plated according to the following procedure. Peritoneal fluid was centrifuged and the resulting pellet resuspended in 5 ml of red blood cell lysis buffer (142 mM NaCl, 118 mM NaEDTA, 1 mM KHCO3 pH 7.4) at room temperature for 4 minutes. An equal volume of cold low glucose growth media was added followed by cell pelleting and resuspension in 37°C low glucose growth media. Cells were counted with the use of a hemocytometer and plated in culture dishes at 5 × 105 cells/ml in low glucose growth media. After 30 min, plates were washed twice to remove non-adherent cells, resulting in approximately 80% pure macrophages, as previously confirmed by CD11b staining and morphology . Immediately following plating selection, peritoneal macrophages were used for uptake experiments.
Cell Culture/Insulin and Glucose Treatment
Raw 264.7 cells were grown in RPMI growth media (2 g/L glucose) as previously described . For glucose and mannitol treatments, cells were resuspended at 2.5 × 105 cells/ml in low glucose growth media (1 g/L glucose) or supplemented with additional glucose or mannitol at the concentrations indicated and grown for 48 h. For chronic insulin treatments, cells were treated as above with or without the addition of 1 nm insulin or at the concentrations indicated for 48 h. Cell viability was at least 80% as determined by PI staining.
Quantitative analysis of macropinocytosis was performed as described [13, 43, 44], with minor modifications. Cells (2.5 × 105) were incubated with 5 μg/mL FITC-albumin at 37°C for 4 h. Macropinocytosis was stopped by 3 washes in ice-cold wash buffer. Gates were set to exclude PI positive cells. For PI3-kinase inhibition experiments, 25 μM LY294002 or wortmannin (10 nM or 100 nM) was added 15 m prior to uptake experiments. For inhibition of actin polymerization studies, 1–10 μM of cytochalasin D was added 15 m prior to uptake studies. For PKC inhibition studies, 10 μM bisindolylmaleimide or 0.25–5 μM rottlerin was added 15 m prior to uptake experiments. For leptin experiments, 6–620 nM leptin was added 48 h prior to uptake experiments. For AICAR experiments, 50–1000 μM AICAR was added 48 h prior to uptake experiments. For compound C experiments, 1 μM compound C was added 48 h prior to uptake experiments. For fluorescent imaging studies cell grown in Culture Micro Slides and treated as indicated. Cells were fixed with 10% formalin for 15 m and coverslipped with Fluormount G. Cells were then visualized using the FITC filter.
Macrophages were lysed in ice-cold lysis buffer and proteins resolved by SDS-PAGE (25 μg/lane) under reducing conditions in 4–20% gradient gels. After electrotransfer to nitrocellulose and resolution of proteins with ECL Plus Kit (Amersham) , bands where quantified by densitometry and analyzed using Image J (NIH), The numerical data reported in the 'results' section is based on the summary of all blots followed by statistical analysis.
Data are presented as mean ± SEM. Experimental data were analyzed either by the Student's t-test for comparison of means, or by ANOVA using Excel (Microsoft, Redmond WA). Statistical significance was denoted at p < 0.05.
We thank Sarah Assian for her assistance acquiring data and Dr. Barbara Pilas and Ben Montez with the Keck Biotechnology Center Flow Cytometry Facility for their help conducting flow cytometry experiments and Dr. Sally Rousey for reviewing the manuscript. This research was supported by grants from the National Institutes of Health (DK064862 and NS58525 to G.G.F and Ruth Kirschstein Institutional National Research Service Award 5T32 DK59802 to the Division of Nutritional Sciences and Predoctoral Fellowship to C.B.G.) and the University of Illinois Agricultural Experiment Station (to G.G.F.).
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