Fatty acid binding proteins, FABPs, have been identified as central regulators of both metabolic and inflammatory pathways. FABPs act as intracellular receptors for a variety of hydrophobic compounds, enabling their diffusion within the cytoplasmic compartment. We have shown that adipocyte FABP (A-FABP) and epithelial FABP (E-FABP) regulate macrophage cholesterol trafficking and inflammatory function, in part via regulation of the activity of the peroxisome proliferator-activated receptor (PPAR-?). Macrophages and dendritic cells (DC) from FABP- deficient mice are defective in expression of proinflammatory cytokines and are inefficient in the promotion of proinflammatory T cells responses during antigen presentation. FABP-deficient mice are protected from development of experimental autoimmune encephalomyelitis (EAE). Overall, the results of our research suggest that FABPs regulate a molecular switch between metabolic and inflammatory pathways in macrophages and DC and, as a consequence, regulate both innate and adaptive immune responses. We will continue our studies of these proteins through the pursuit of the following specific aims:
Specific Aim 1 is to identify the molecular mechanism(s) by which FABPs affect inflammatory cytokine gene expression in macrophages and DC. We have found that FABP-deficiency is accompanied by elevated activity of AMP- activated protein kinase (AMPK) and that AMPK is a negative regulator of macrophage inflammatory function. Experiments will be performed to determine the link between FABPs, AMPK, and PPAR-? testing the hypothesis that FABP regulation of energy stores regulates AMPK activity, which in turn modulates inflammatory activity.
Specific Aim 2 is to further delineate the impact of FABP-deficiency on autoimmune disease using EAE as a model.
This aim will include an evaluation of the specific contributions of T cell priming, and of the tissue environment, towards the protection from EAE displayed by FABP-deficient mice. In this aim we will also test the in vivo efficacy of inhibitors of FABPs as an anti-inflammatory therapy using the EAE model.
Specific Aim 3 is to test the hypothesis that the expression of FABPs links dietary fat intake with exacerbated inflammatory disease. We will evaluate the effects of fat intake on FABP expression in leukocyte populations and the association of diet-induced FABP expression with inflammatory responsiveness. The completion of these studies will provide a more comprehensive understanding of how FABPs regulate immune and inflammatory responses.
Fatty acid-binding proteins (FABPs) have been shown to play a role in obesity and Type 2 diabetes. This proposal is based on studies demonstrating that FABPs also strongly promote inflammation and contribute to autoimmune inflammatory disease. The goals of the project are to determine the mechanisms by which FABPs regulate inflammatory function in leukocytes and to test the hypothesis that FABPs constitute an accessible and effective target for treatment of inflammatory disease. Given the recent identification of small molecule inhibitors of FABP function, this project has direct relevance to human health.
|Rao, Enyu; Zhang, Yuwen; Li, Qiang et al. (2016) AMPK-dependent and independent effects of AICAR and compound C on T-cell responses. Oncotarget 7:33783-95|
|Zhu, Yanfang Peipei; Brown, Jonathan R; Sag, Duygu et al. (2015) Adenosine 5'-monophosphate-activated protein kinase regulates IL-10-mediated anti-inflammatory signaling pathways in macrophages. J Immunol 194:584-94|
|Rao, Enyu; Zhang, Yuwen; Zhu, Ganqian et al. (2015) Deficiency of AMPK in CD8+ T cells suppresses their anti-tumor function by inducing protein phosphatase-mediated cell death. Oncotarget 6:7944-58|
|Rao, Enyu; Singh, Puja; Li, Yan et al. (2015) Targeting epidermal fatty acid binding protein for treatment of experimental autoimmune encephalomyelitis. BMC Immunol 16:28|
|Carroll, Kelly Casey; Viollet, Benoit; Suttles, Jill (2013) AMPKÎ±1 deficiency amplifies proinflammatory myeloid APC activity and CD40 signaling. J Leukoc Biol 94:1113-21|
|Vladykovskaya, Elena; Ozhegov, Evgeny; Hoetker, J David et al. (2011) Reductive metabolism increases the proinflammatory activity of aldehyde phospholipids. J Lipid Res 52:2209-25|
|Ghare, Smita; Patil, Madhuvanti; Hote, Prachi et al. (2011) Ethanol inhibits lipid raft-mediated TCR signaling and IL-2 expression: potential mechanism of alcohol-induced immune suppression. Alcohol Clin Exp Res 35:1435-44|
|Thompson, Brian R; Mazurkiewicz-Munoz, Anna M; Suttles, Jill et al. (2009) Interaction of adipocyte fatty acid-binding protein (AFABP) and JAK2: AFABP/aP2 as a regulator of JAK2 signaling. J Biol Chem 284:13473-80|
|Sag, Duygu; Carling, David; Stout, Robert D et al. (2008) Adenosine 5'-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J Immunol 181:8633-41|
|Stout, Robert D; Suttles, Jill (2005) Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes. Immunol Rev 205:60-71|
Showing the most recent 10 out of 12 publications