Impaired phagocytosis by alveolar macrophages from diabetic rats is related to the deficient coupling of LTs to the FcgR signaling cascade

Diabetic individuals are more susceptible to infections and this seems to be related to impaired phagocyte function. Alveolar macrophages (AMs) are the first barrier to prevent respiratory infections. Leukotrienes (LTs) increase AM phagocytic activity via FcgR. In this study, we compared AMs from diabetic and non-diabetic rats for phagocytosis via FcgR and the roles of LTs and insulin. Diabetes was induced in male Wistar rats by alloxan (42 mg/kg, i.v.); macrophages were obtained by bronchoalveolar lavage and IgG-opsonised sheep red blood cells (IgG-SRBC) were used as targets. LTs were added to the AMs 5 min before the addition of IgG-SRBC. AMs were treated with a LT synthesis inhibitor (zileuton, 10 kM), or antagonists of the LTB sub(4) receptor (CP105.696, 10 kM) or cys-LT receptor (MK571, 10 kM), 30 or 20 min before the addition of IgG-SRBC, respectively. We found that the phagocytosis of IgG-SRBC by AMs from diabetic rats is impaired compared with non-diabetic rats. Treatment with the LT inhibitor/antagonists significantly reduced AM phagocytosis in non-diabetic but not diabetic rats. During the phagocytosis of IgG-SRBC LTB sub(4) and LTC sub(4) were produced by AMs from both groups. The addition of exogenous LTB sub(4) or LTD sub(4) potentiated phagocytosis similarly in both groups. Phagocytosis was followed by the phosphorylation of PKC-d, ERK and Akt. This was reduced by zileuton treatment in AMs from non-diabetic but not diabetic rats. The addition of insulin to AMs further increased the phagocytosis by increasing PKC-d phosphorylation. These results suggest that the impaired phagocytosis found in AMs from diabetic rats is related to a deficient coupling of LTs to the FcgR signaling cascade and that insulin has a key role in this coupling. An essential role for insulin in innate immunity is suggested.