Abstract
BackgroundMacrophages (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.ResultsThe 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.ConclusionTaken 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.
Highlights
Macrophages (MΦs) utilize macropinocytosis to integrate immune and metabolic signals in order to initiate an effective immune response
A, peritoneal MΦs were isolated from non-diabetic and diabetic and FITC-albumin uptake was measured by flow cytometry.B, MΦs were cultured in high glucose/high insulin conditions for 24 h or 48 h
Peritoneal MΦs from diabetic mice and MΦs cultured in diabetic conditions have decreased macropinocytosis To determine if MΦ macropinocytosis was affected by diabetes, peritoneal MΦs were isolated from diabetic db/db mice and from non-diabetic db/+ mice and macropinocytosis was tested
Summary
Macrophages (MΦs) utilize macropinocytosis to integrate immune and metabolic signals in order to initiate an effective immune response. 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 PI3kinase dependent rearrangement of the plasma membrane [2,3]. 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. The peptides are processed and, in the case of professional antigen presenting cells, these peptides are shuttled back to the cell membrane in (page number not for citation purposes)
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