Abstract 441: Macrophage CD40 in Atherosclerosis, Obesity and Multiple Sclerosis

Introduction: The co-stimulatory dyad CD40-CD40L plays a central role in fine-tuning immune reactions in atherosclerosis, obesity-induced inflammation and multiple sclerosis (MS). Inhibition of CD40 in atherosclerosis and experimental autoimmune encephalomyelitis (EAE) ameliorates disease outcome, whereas CD40-deficiency in a diet induced obesity (DIO) model worsens insulin resistance and induces excessive adipose tissue inflammation. Although inhibition of CD40 has powerful effects, we do not know which CD40 expressing cell-type is responsible for the amelioration/aggravation of disease. As myeloid CD40 is known to play a role in leukocyte trafficking, which is important in atherosclerosis, obesity and neuro-inflammation, we hypothesize that myeloid CD40 is important in these disease modalities. Methods: To investigate the role of myeloid CD40 in atherosclerosis, obesity and EAE we have generated macrophage specific LysM-CD40flfl - (ApoE-/-), and dendritic cell/adipose tissue macrophage specific CD11C-CD40flfl). Atherosclerosis was induced by aging the LysM-CD40flfl - ApoE-/- mice until 30 weeks. EAE was induced in LysM-CD40flfl mice by subjecting them to myelin oligodendrocyte glycoprotein peptide (MOG35-55), and LysM-CD40flfl and CD11c-CD40flfl mice were subjected to a 60% high fat diet for 18 wks. Results: LysM-CD40flfl - ApoE-/- mice showed a significant reduction in atherosclerotic plaque area, with a reduced macrophage accumulation. Loss of macrophage CD40 in EAE results in a significant decrease in the neurological symptoms of EAE, and a majority of the LysM-CD40flfl mice were fully protected against EAE. LysM-CD40flfl mice subjected to DIO showed an increase in macrophage accumulation in the visceral adipose tissue, but did not affect adipose tissue mass, insulin tolerance, or plasma triglyceride concentrations. The CD11CcreCD40flfl mice exhibited a decrease in visceral adipose tissue weight, an increased lipid content in the liver and slightly decreases leukocyte numbers and pro-inflammatory gene expression in the adipose tissue. Conclusions: Macrophage CD40 is an important driver of atherosclerosis and EAE. Macrophage CD40 is protective in obesity-induced inflammation, but is probably not the key player.