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Review
. 2008 Jun;7(3):254-69.
doi: 10.2174/187152708784936671.

Role of secretory phospholipase a(2) in CNS inflammation: implications in traumatic spinal cord injury

W Lee Titsworth  1 , Nai-Kui Liu, Xiao-Ming Xu
Affiliations
Review

Role of secretory phospholipase a(2) in CNS inflammation: implications in traumatic spinal cord injury

W Lee Titsworth et al. CNS Neurol Disord Drug Targets. 2008 Jun.

Abstract

Secretory phospholipases A(2) (sPLA(2)s) are a subfamily of lipolytic enzymes which hydrolyze the acyl bond at the sn-2 position of glycerophospholipids to produce free fatty acids and lysophospholipids. These products are precursors of bioactive eicosanoids and platelet-activating factor (PAF). The hydrolysis of membrane phospholipids by PLA(2) is a rate-limiting step for generation of eicosanoids and PAF. To date, more than 10 isozymes of sPLA(2) have been found in the mammalian central nervous system (CNS). Under physiological conditions, sPLA(2)s are involved in diverse cellular responses, including host defense, phospholipid digestion and metabolism. However, under pathological situations, increased sPLA(2) activity and excessive production of free fatty acids and their metabolites may lead to inflammation, loss of membrane integrity, oxidative stress, and subsequent tissue injury. Emerging evidence suggests that sPLA(2) plays a role in the secondary injury process after traumatic or ischemic injuries in the brain and spinal cord. Importantly, sPLA(2) may act as a convergence molecule that mediates multiple key mechanisms involved in the secondary injury since it can be induced by multiple toxic factors such as inflammatory cytokines, free radicals, and excitatory amino acids, and its activation and metabolites can exacerbate the secondary injury. Blocking sPLA(2) action may represent a novel and efficient strategy to block multiple injury pathways associated with the CNS secondary injury. This review outlines the current knowledge of sPLA(2) in the CNS with emphasis placed on the possible roles of sPLA(2) in mediating CNS injuries, particularly the traumatic and ischemic injuries in the brain and spinal cord.

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Figures

Fig. (1)
Fig. (1). Classification of the mammalian PLA2 isoforms
The top panel shows a branching diagram indicating the relative subdivisions of the PLA2 subfamily and their years of discovery. The mammalian PLA2 family of enzymes is grossly divided into the sPLA2, cPLA2, iPLA2, and PAF-AH. The sPLA2 subfamily is further divided into groups IB, group II and V, group X, and group III and XII based on structural and functional differences presented in the table below. HSPG: heparin sulfate proteoglycans.
Fig. (2)
Fig. (2). Intracellular handling and sPLA2 activity
Following stimulation by various cytokines [1], sPLA2 is synthesized in the nucleus [2] and endoplasmic reticulum prior to packaging for secretion in the Golgi apparatus [3]. It is within the Golgi apparatus and later microvesicles that certain isoforms, particularly IIA, are predominantly active. Following secretion [4], sPLA2 can metabolize the extracellular lipid membrane directly, bind to the sPLA2 receptor (sPLA2-R), and/or be endocytosed via the heparin sulfate proteoglycan shuttle (HSPG shuttle). Of course, each of these actions is governed by species and isoform specificity. The inset shows the general metabolism of phospholipids by sPLA2. sPLA2 first hydrolyzes the acyl bond at the sn-2 position of glycerophospholipids to produce free fatty acids (such as arachidonic acid) and lysophospholipid (Lyso-PL). Arachidonic acid can then be further modified by COX to form prostaglandins, lipoxygenase to form leukotrienes, or cytochrome P450 to form epoxides. Prostaglandins can be further modified to form thromboxanes. These eicosanoids have metabolic activities including proinflammatory and vasoconstrictive functions.
Fig. (3)
Fig. (3). Overview of sPLA2’s role in spinal cord injury
The toxicity of sPLA2 is compounded by three factors. 1) sPLA2 is upregulated by commonly known neurotoxic mechanisms such as oxidative stress, cytokines, and EAA. 2) Both the primary metabolites of sPLA2 activity, such as free fatty acids and lysophospholipids, and the secondary metabolites, such as eicosanoids and platelet activating factor, are toxic to the CNS. 3) Finally, sPLA2 has been shown to reciprocally upregulate oxidative stress, cytokines, and EAA thus propagating a positive feedback loop resulting in cytotoxicity and secondary SCI. It must also be noted that sPLA2 does not work in isolation from cPLA2 and iPLA2, rather a reciprocal activity is often demonstrated among the PLA2 subfamilies.
Fig. (4)
Fig. (4). sPLA2 activity within spinal cord injury
Following SCI, oxidative stress, cytokines, and EAA are upregulated. These toxic factors then upregulate the synthesis of sPLA2. Subsequently sPLA2 mediates the hydrolysis of phospholipids into lysophospholipids (Lyso-PL), such as LPC, and free fatty acids (FFA), such as AA. Independent of other factors, sPLA2 and LPC demyelinate axons in the spinal cord and sPLA2 and AA have been shown to trigger apoptosis in neurons and oligodendrocytes. The metabolism of AA results in increased oxidative stress from lipid peroxidation and increased eicosanoids which have been shown to increase inflammation and ischemia. LPC also increases inflammation while its metabolite, PAF, triggers ischemia. Infiltrating polymorphonuclear neutrophils (N), lymphocytes (L), and macrophages (Mϕ) then flood the CNS with more sPLA2, oxidants, and cytokines thus exacerbating the positive feedback loop, while the upregulation in sPLA2 and LPC trigger the release of EAAs from synaptic terminals.
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