9th Annual BMRP Investigator Meeting - Abstract
Leptin as an Immunomodulatory Target in Crohn’s Disease
Hafid O. Al-Hassi1, David O. Bernardo1, Aravinth U. Murugananthan1, Nicholas R. English1, Ailsa L. Hart1, Alex I.F. Blakemore2 and Stella C. Knight1,a
1Antigen Presentation Research Group, Imperial College London, Northwick Park and St Mark’s Campus (Harrow, United Kingdom); 2Genomic Medicine Group, Imperial College London, Hammersmith Campus (London, United Kingdom)
Increased mesenteric fat, an early characteristic of Crohn’s disease (CD), is accompanied by local increases in proinflammatory adipokine, leptin, which can signal through the long form of its receptor, LEPRb, Dendritic cells (DC) initiate or block immune activity, and after maturation, express CCR7, which is associated with migration to lymph nodes where they initiate immune responses. Leptin up regulated expression of CCR7 on DC from blood and colon, which was functional as indicated from increased migration towards MIP3b in chemotaxis assays; probiotic bifidobacteria blocked CCR7 upregulation. Furthermore, leptin produced increased lipid in DC indicating a role for lipid in DC activity. Increase in phosphorylated STAT3 on DC incubation with leptin suggested that leptin acted via LEPRb. LEPRb and CCR7 were expressed on fresh normal ileal DC,but on blood and colonic DC were only plentiful in CD. RT-PCR confirmed differences in LEPRb expression. Constitutive ileal DC expression of LEPRb and CCR7 was not related to maturation; normal ileal DC, like colonic DC, were immature by flow cytometry, immunohistochemistry and electron microscopy. Thus, there is co-incident DC expression of LEPRb and CCR7 and multiple effects of leptin on DC including up regulation of CCR7. Leptin may control DC function and migration from gut in homeostatic conditions in ileum, and during inflammation in colon. Leptin/leptin receptors could, therefore, be treatment targets in CD.
a Principal Investigator