Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis

Abstract

The arachidonic acid (AA) cascade produces eicosanoids, such as prostaglandins (PGs), that regulate physiological and pathological functions. Although various nonsteroidal anti-inflammatory drugs have been developed, blocking upstream components (cyclooxygenase-1 and -2) of the AA cascade leads to severe side effects, including gastrointestinal ulcers and cardiovascular events, respectively, due to the complexity of the AA cascade. Here, using an AA cascade-targeted lipidomics approach, we report that microsomal PGE synthase 1 (mPGES-1) plays a key role in experimental autoimmune encephalomyelitis (EAE). Eicosanoids (mainly PGD 2) are produced constitutively in the spinal cord of naive mice. However, in EAE lesions, the PGE 2 pathway is favored and the PGD2, PGI2, and 5-lipoxygenase pathways are attenuated. Furthermore, mPGES-1 ؊/؊ mice showed less severe symptoms of EAE and lower production of IL-17 and IFN-␥ than mPGES-1 ؉/؉ mice. Expression of PGE2 receptors (EP1, EP2, and EP4) was elevated in EAE lesions and correlated with clinical symptoms. Immunohistochemistry on central nervous systems of EAE mice and multiple sclerosis (MS) patients revealed overt expression of mPGES-1 protein in microglia/macrophages. Thus, the mPGES-1-PGE 2-EPs axis of the AA cascade may exacerbate EAE pathology. Our findings have important implications for the design of therapies for MS.autoimmunity ͉ demyelination ͉ lipid mediator ͉ mass spectrometry ͉ Th17

Converse regulation of CCR7‐driven human dendritic cell migration by prostaglandin E2 and liver X receptor activation

“…Deregulated PGE 2 production can contribute to severe immune inflammation resulting in tissue damage, autoimmune diseases through Th1 and Th17 cell differentiation, or tumorigenesis [11,[15][16][17]. However, under physiological conditions, PGE 2 is also known to be necessary for initiating immune responses, e.g.…”

“…However, sustained PGE 2 -mediated activation of EP4 in T cells and DCs promotes Th1 and Th17 differentiation and expansion, thereby promoting severe autoimmune diseases [15,16]. Of note, mice lacking the inflammatory microsomal PGE 2 synthase 1 (mPGES1) show reduced symptoms of experimental autoimmune encephalomyelitis, whereas mPGES1 is highly expressed at autoinflammatory sites in multiple sclerosis patients [17].…”

Pathogenesis and Progression of Multiple Sclerosis: The Role of Arachidonic Acid–Mediated Neuroinflammation

“…In the EAE model, the upstream enzyme cPLA 2 has been shown to play a key role in the pathogenesis of the disease as cPLA 2 knockout mice and naïve mice treated with a cPLA 2 specific inhibitor were both resistant to EAE induction (25,26). Downstream cPLA 2 , COX-2, inducible PGE 2 synthase, and PGE 2 levels were all increased in the brain of EAE mice (27). COX-2 was expressed in the resident microglia, infiltrating macrophages, and endothelial cells of the brain of EAE mice (28)(29).…”

Lipid Mediators in Life Science

“…Moreover, mPGES-1 deficiency is associated with impaired fracture healing in mouse models of skeletal disorders [90], indicating its role in bone metabolism. in experimental autoimmune encephalomyelitis (EaE), a mouse model of multiple sclerosis that is the most prevalent T H1 /T H17 -mediator autoimmune disorder of the CNS with neurological symptoms caused by inflammation and demyelination, Ptges -/-mice show less severe symptoms of EaE and lower production of iL-17 and iFN-γ than wild-type mice [30]. PGE 2 , acting on its receptor EP4 on T cells and dendritic cells, facilitates T H1 cell differentiation and amplifies IL-23-mediated T H17 cell expansion, and administration of an EP4-selective antagonist in vivo decreases accumulation of both T H1 and T H17 cells in regional lymph nodes and suppresses the disease progression in mice subjected to EaE or contact hypersensitivity [91].…”