Sphingolipids: a potential molecular approach to treat allergic inflammation

Abstract

Allergic inflammation is an immune response to foreign antigens, which begins within minutes of exposure to the allergen followed by a late phase leading to chronic inflammation. Prolonged allergic inflammation manifests in diseases such as urticaria and rhino-conjunctivitis, as well as chronic asthma and life-threatening anaphylaxis. The prevalence of allergic diseases is profound with 25% of the worldwide population affected and a rising trend across all ages, gender, and racial groups. The identification and avoidance of allergens can manage this disease, but this is not always possible with triggers being common foods, prevalent air-borne particles and only extremely low levels of allergen exposure required for sensitization. Patients who are sensitive to multiple allergens require prophylactic and symptomatic treatments. Current treatments are often suboptimal and associated with adverse effects, such as the interruption of cognition, sleep cycles, and endocrine homeostasis, all of which affect quality of life and are a financial burden to society. Clearly, a better therapeutic approach for allergic diseases is required. Herein, we review the current knowledge of allergic inflammation and discuss the role of sphingolipids as potential targets to regulate inflammatory development in vivo and in humans. We also discuss the benefits and risks of using sphingolipid inhibitors.

Figure 1

Histamine receptors on ECs. Two histamine receptors (H₁ and H₂) are found on ECs. Within minutes of histamine binding to its receptors, the G-protein subunits are activated to initiate intracellular signalling. The αq subunit of the G-protein contributes to reduced cAMP accumulation, induced ERK1/2, and induced inositol phospholipid (PI3K) signalling. The β and γ subunits contribute to the activation of NFκB and subsequent translocation into the nucleus where transcriptional processes are regulated causing cellular changes, such as vascular contraction and permeability, all of which are important for immune regulation and inflammation.

Figure 2

Sphingomyelin pathway. Sphingomylein is hydrolysed to ceramide, which is then metabolized to sphingosine and sphingosine-1 phosphate (S1P) by different kinases (green). This process is reversible via the activities of different synthases and phosphatases (red). The levels of the biological product, S1P, are regulated by S1P lyase which degrades it into hexadecanal and phosphoethanolamine. Although the structures of each sphingolipid are similar, they have divergent cellular functions with ceramide and sphingoine being pro-apoptotic, and S1P being prosurvival.

Figure 3

Intracellular SK-1 and SK-2 activity. The activation of SK-1 and SK-2 occurs via ERK1/2 phosphorylation in response to proinflammatory mediators, such as histamine and TNFα. Upon the activation, SK-1 is translocated from the cytoplasm to plasma membrane where it catalyses sphingosine to form S1P. S1P can then be transported outside the cell and then act back on its receptors to induce the activation of G-proteins for subsequent cellular changes, such as survival, proliferation, and migration. In contrast, SK-2 activity is associated primarily with the nuclear membrane, where it is phosphorylated prior to being translocated out of the nucleus. At the nuclear membrane and endoplasmic reticulum, S1P can be dephosphorylated to sphingosine and ceramide via the sphingolipid salvage pathway where many enzymes including sphingomyelinases, cerebrosidases, ceramides, and ceramide synthases are involved to induce apoptosis.

Figure 4

. Exocytosis of P-selectin by ECs. P-selectin is preformed and stored in Weibel Palade bodies (WPBs). It is found to be solely present or co-stored in WPBs with von Willebrand Factor (vWF) or angiopoietins (Ang). Upon extracellular stimulation, WPBs exocytose to the cell surface via the activation of Ral-GTP from Ral-GDP. WPB-containing vWF is also driven and translocated to the plasma membrane by SNARE. The rapid surface expression of P-selectin mediates the initial recruitment of leukocytes to ECs by rolling and tethering, which is important during the early development of allergic inflammation.