How do sphingosine-1-phosphate affect immune cells to resolve inflammation?

Abstract

Inflammation is an important immune response of the body. It is a physiological process of self-repair and defense against pathogens taken up by biological tissues when stimulated by damage factors such as trauma and infection. Inflammation is the main cause of high morbidity and mortality in most diseases and is the physiological basis of the disease. Targeted therapeutic strategies can achieve efficient toxicity clearance at the inflammatory site, reduce complications, and reduce mortality. Sphingosine-1-phosphate (S1P), a lipid signaling molecule, is involved in immune cell transport by binding to S1P receptors (S1PRs). It plays a key role in innate and adaptive immune responses and is closely related to inflammation. In homeostasis, lymphocytes follow an S1P concentration gradient from the tissues into circulation. One widely accepted mechanism is that during the inflammatory immune response, the S1P gradient is altered, and lymphocytes are blocked from entering the circulation and are, therefore, unable to reach the inflammatory site. However, the full mechanism of its involvement in inflammation is not fully understood. This review focuses on bacterial and viral infections, autoimmune diseases, and immunological aspects of the Sphks/S1P/S1PRs signaling pathway, highlighting their role in promoting intradial-adaptive immune interactions. How S1P signaling is regulated in inflammation and how S1P shapes immune responses through immune cells are explained in detail. We teased apart the immune cell composition of S1P signaling and the critical role of S1P pathway modulators in the host inflammatory immune system. By understanding the role of S1P in the pathogenesis of inflammatory diseases, we linked the genomic studies of S1P-targeted drugs in inflammatory diseases to provide a basis for targeted drug development.

Keywords: S1P; SphKs; immune cells; inflammation; signal pathway.

Figure 1

The two Sphks play different roles. Sphk1, which exists in the cytoplasm, is activated and produces S1P, which can directly act on macrophages, cause the production of interleukin 1-β, the release of NLRP3 inflammasome and the activation of pro-inflammatory signaling pathway (NF-κB pathway), aggravating inflammatory response. At the same time, under the action of SPHK1 in the cytoplasm, S1P increases the level of S1P in the blood circulation, oxidative stress leads to increased permeability, causes vascular endothelial leakage, and is characterized by pro-inflammatory effect. While Sphk2, which exists in the nucleus, is activated and produces S1P, which directly acts on intestinal epithelial cells, inhibits the activation of pro-inflammatory signaling pathway (NF-κB pathway), and reduces inflammatory response. SPHK2 can reduce the level of S1P in the blood circulation, act on CD11b macrophages, inhibit the STING signaling pathway to reduce acute lung injury. In addition, up-regulation of Sphk2 can increase the level of S1P in the nucleus, leading to M1 differentiation of macrophages and the increase of NLRP3 inflammasome. Therefore, SPHK2 has both pro-inflammatory and anti-inflammatory effects.

Figure 2

S1P is synthesized from serine and palmitoyl-CoA by a de novo pathway or from the ubiquitous membrane lipid sphingolipia (SMD). Sphingosine is produced by hydrolysis of ceramides, which can be recycled by acylation, a process known as the “rescue pathway” that can lead to ccramide regeneration. In the cell membrane and cytoplasm, sphinganine is converted to S1P by sphinganine kinases (SphKs). Finally, SIP is cleaved by SIP cleaver (SPL) or dephosphorylated to hexadecaneal and phosphothanolamine.

Figure 3

The distribution of S1P is strictly controlled and involved in innate and adaptive immunity. S1P is distributed in low concentration in organ tissues, and in the blood circulation, S1P presents the characteristics of high-level distribution. In the innate immune response, S1P plays a role through the receptors on various immune cells, such as in TLRS, activating the NF-KB signaling pathway, promoting the release of a variety of pro-inflammatory factors, inhibiting immune responses in macrophages, and reducing migration and apoptosis in neutrophils. In the adaptive immune response, under the action of APC, T cells are differentiated and produce anti-inflammatory effects. In addition, S1P inhibits LPS-induced B cell inflammatory responses and promotes B cell migration and transport.