Inflammatory Ocular Diseases and Sphingolipid Signaling

Abstract

Inflammation is a powerful immune countermeasure to tissue damage and infection. The inflammatory response is complex and requires the involvement of myriad signaling pathways and metabolic processes, all governed by a multitude of regulatory systems. Although inflammation is a vital defense against tissue injury and a necessary step in tissue healing, the mechanisms which modulate the initiation, intensity, and duration of this innate immune response can malfunction and result in inappropriate or out-of-control inflammation, even in the absence of an appropriate stimulus. Though the human eye exists in an immune-privileged microenvironment, it is not spared from this. The eye is neither devoid of immune cells nor is it fully sequestered from systemic immune responses, and is therefore fully capable of ruining itself through localized inflammatory dysfunction and systemic inflammatory disease (Taylor AW, Front Immunol 7:37, 2016; Zhou R, Caspi RR, Biol Rep 2, 2010). In fact, a wide range of ocular inflammatory diseases exist and are major causes of blindness in humans. Advances in the understanding of inflammatory processes have revealed new key pathways and molecular factors involved in the mechanisms of inflammation. Lipids and sphingolipids are increasingly being recognized as having important signaling roles in the pathophysiology of ocular inflammatory diseases. What follows below is a discussion of fundamental inflammatory processes, the place of sphingolipids as mediators of said processes, brief descriptions of major inflammatory ocular diseases, and new findings implicating sphingolipids in their pathogenesis.

Keywords: Glaucoma; Glucosylceramide; Innate immunity; Ocular inflammtion; S1P receptors; Sphingolipid signaling; Sphingosine 1-phosphate; Uveitis.

Fig. 8.1

Schematic representation of cellular sphingolipid metabolism. Ceramide (Cer) is produced primarily in the endoplasmic reticulum (ER) from serine and palmitoyl-CoA via a series of reactions in the de novo pathway. Cer is then either converted to Galactosylceramide (GalCer) by addition of a galactose or transported from the ER to the trans-Golgi, possibly via a trafficking mechanism mediated by Cer Transfer Protein (CERT). In the Golgi, Cer is either converted to Sphingomyelin (SM) by Sphingomyelin Synthase (SMS), or is glycosylated to form Glucosylceramide (GlcCer) by GlcCer Synthase (GCS). GlcCer may be converted to Lactosylceramide (LacCer) by addition of galactose with LacCer Synthase (LCS). SM from the Golgi is transported to the plasma membrane, where it may be converted by cytosolic neutral sphingomyelinase (nSMase) back to Cer, which is phosphorylated by Cer Kinase (CerK) to ceramide 1-phosphate (C1P). Alternatively, SM may be converted to Cer via secretory SMase (sSMase), which is converted to Sphingosine (Sph) by neutral ceramidase (nCDase). Sph is phosphorylated to sphingosine 1-phosphate (S1P) by Sphingosine Kinase (SphK) 1 or 2, which can signal extracellularly via membrane-bound S1P receptors (of which there are 5 known). Complex sphingolipids from the plasma membrane may enter the endolysosomal pathway and be hydrolyzed back to Cer, which is converted to Sph within the lysosome by acid ceramidase (aCDase or ASAH1, N-Acylsphingosine Amidohydrolase 1). From here, Sph is either phosphorylated to S1P or re-acylated back to Cer by Ceramide Synthase (CerS) in the salvage pathway. S1P leaves the sphingolipid metabolic pathway by conversion to ethanolamine phosphate and hexadecenal by Sphingosine 1-Phosphate Lyase (S1PL)

Fig. 8.2

Brief summary of major sphingolipid classes and notable effects relevant to inflammatory ocular diseases. Cer ceramide, Sph sphingosine, Glc glucose, Gal galactose, P phosphate