Sphingolipids, which are components of cellular membranes and organ tissues, can be synthesized or degraded to modulate cellular responses according to environmental cues, and the balance among the different sphingolipids is important for directing immune responses, regardless of whether they originate, as intra- or extracellular immune events. Recent progress in multiomics-based analyses and methodological approaches has revealed that human health and diseases are closely related to the homeostasis of sphingolipid metabolism, and disease-specific alterations in sphingolipids and related enzymes can be prognostic markers of human disease progression. Accumulating human clinical data from genome-wide association studies and preclinical data from disease models provide support for the notion that sphingolipids are the missing pieces that supplement our understanding of immune responses and diseases in which the functions of the involved proteins and nucleotides have been established. In this review, we analyze sphingolipid-related enzymes and reported human diseases to understand the important roles of sphingolipid metabolism. We discuss the defects and alterations in sphingolipid metabolism in human disease, along with functional roles in immune cells. We also introduce several methodological approaches and provide summaries of research on sphingolipid modulators in this review that should be helpful in studying the roles of sphingolipids in preclinical studies for the investigation of experimental and molecular medicines.

The roles of neutrophils in renal inflammation are currently unclear. On examining these cells in the unilateral ureteral obstruction murine model of chronic kidney disease, we found that the injured kidney bore a large and rapidly expanding population of neutrophils that expressed the eosinophil marker Siglec-F. We first verified that these cells were neutrophils. Siglec-F⁺ neutrophils were recently detected in several studies in other disease contexts. We then showed that a) these cells were derived from conventional neutrophils in the renal vasculature by TGF-β1 and GM-CSF; b) they differed from their parent cells by more frequent hypersegmentation, higher expression of profibrotic inflammatory cytokines, and notably, expression of collagen 1; and c) their depletion reduced collagen deposition and disease progression, but adoptive transfer increased renal fibrosis. These findings have thus unveiled a subtype of neutrophils that participate in renal fibrosis and a potentially new therapeutic target in chronic kidney disease.

We determined the function of phospholipase D2 (PLD2) in host defense in highly lethal mouse models of sepsis using PLD2^−/− mice and a PLD2-specific inhibitor. PLD2 deficiency not only increases survival but also decreases vital organ damage during experimental sepsis. Production of several inflammatory cytokines (TNF, IL-1β, IL-17, and IL-23) and the chemokine CXCL1, as well as cellular apoptosis in immune tissues, kidney, and liver, are markedly decreased in PLD2^−/− mice. Bactericidal activity is significantly increased in PLD2^−/− mice, which is mediated by increased neutrophil extracellular trap formation and citrullination of histone 3 through peptidylarginine deiminase activation. Recruitment of neutrophils to the lung is markedly increased in PLD2^−/− mice. Furthermore, LPS-induced induction of G protein–coupled receptor kinase 2 (GRK2) and down-regulation of CXCR2 are markedly attenuated in PLD2^−/− mice. A CXCR2-selective antagonist abolishes the protection conferred by PLD2 deficiency during experimental sepsis, suggesting that enhanced CXCR2 expression, likely driven by GRK2 down-regulation in neutrophils, promotes survival in PLD2^−/− mice. Furthermore, adoptively transferred PLD2^−/− neutrophils significantly protect WT recipients against sepsis-induced death compared with transferred WT neutrophils. We suggest that PLD2 in neutrophils is essential for the pathogenesis of experimental sepsis and that pharmaceutical agents that target PLD2 may prove beneficial for septic patients.

Severe sepsis, a principal cause of death in intensive care units, occurs when host immune defenses fail to combat invading microbes. In this paper, we report that the administration of peptide agonists of formyl peptide receptors, including Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm), protected against death by enhanced bactericidal activity and inhibition of vital organ inflammation and immune cell apoptosis in a cecal ligation and puncture (CLP) sepsis mouse model. The administration of WKYMVm also enhanced the production of type 1 (IFN-γ and IL-12) and type 17 (IL-17 and TGF-β) cytokines in CLP mice. In contrast, the administration of WKYMVm inhibited the production of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) in the CLP mice. The therapeutic and bactericidal effects of WKYMVm were partly reversed in IFN-γ–deficient mice, whereas target organ inflammation was not. Meanwhile, the therapeutic and anti-inflammatory effects of WKYMVm were partly reversed in IL-17–deficient mice. In addition, the administration of WKYMVm also enhanced type 1 and type 17 Th cell responses in mice sensitized with LPS plus Ags. These results suggest that the agonists of formyl peptide receptors effectively prevent development of severe sepsis following microbial infection partly via augmentation of type 1 and type 17 immune responses.

Wnt5a is a ligand that activates the noncanonical Wnt signaling pathways (β-catenin-independent pathways). Human neutrophils expressed several Wnt5a receptors, such as Frizzled 2, 5 and 8. Stimulation of human neutrophils with Wnt5a caused chemotactic migration and the production of two important chemokines, CXCL8 and CCL2. CCL2 production by Wnt5a was mediated by a pertussis toxin-sensitive G-protein-dependent pathway. Wnt5a also stimulated the phosphorylation of three mitogen-activated protein kinases (MAPKs: ERK, p38 MAPK and JNK) and Akt. Inhibition of ERK, p38 MAPK or JNK by specific inhibitors induced a dramatic reduction in Wnt5a-induced CCL2 production. Supernatant collected from lipopolysaccharide-stimulated macrophages induced neutrophil chemotaxis, which was significantly inhibited by anti-Wnt5a antibody. Our results suggested that Wnt5a may contribute to neutrophil recruitment, mediating the inflammation response.

Formyl peptide receptors (FPRs) belong to the G protein-coupled receptor (GPCR) family and are well known as chemotactic receptors and pattern recognition receptors (PRRs) that recognize bacterial and mitochondria-derived formylated peptides. FPRs are also known to detect a wide range of ligands, including host-derived peptides and lipids. FPRs are highly expressed not only in phagocytes such as neutrophils, monocytes, and macrophages but also in nonhematopoietic cells such as epithelial cells and endothelial cells. Mucosal surfaces, including the gastrointestinal tract, the respiratory tract, the oral cavity, the eye, and the reproductive tract, separate the external environment from the host system. In mucosal surfaces, the interaction between the microbiota and host cells needs to be strictly regulated to maintain homeostasis. By sharing the same FPRs, immune cells and epithelial cells may coordinate pathophysiological responses to various stimuli, including microbial molecules derived from the normal flora. Accumulating evidence shows that FPRs play important roles in maintaining mucosal homeostasis. In this review, we summarize the roles of FPRs at mucosal surfaces.