Sphingosine-1-Phosphate (S1P) and S1P Signaling Pathway: Therapeutic Targets in Autoimmunity and Inflammation
2016; 76 (11): 1067-1079
Effects of sphingosine-1-phosphate receptor 1 phosphorylation in response to FTY720 during neuroinflammation.
2016; 1 (9)
Sphingosine-1-phosphate (S1P) and S1P receptors (S1PR) are ubiquitously expressed. S1P-S1PR signaling has been well characterized in immune trafficking and activation in innate and adaptive immune systems. However, the full extent of its involvement in the pathogenesis of autoimmune diseases is not well understood. FTY720 (fingolimod), a non-selective S1PR modulator, significantly decreased annualized relapse rates in relapsing-remitting multiple sclerosis (MS). FTY720, which primarily targets S1P receptor 1 as a functional antagonist, arrests lymphocyte egress from secondary lymphoid tissues and reduces neuroinflammation in the central nervous system (CNS). Recent studies suggest that FTY720 also decreases astrogliosis and promotes oligodendrocyte differentiation within the CNS and may have therapeutic benefit to prevent brain atrophy. Since S1P signaling is involved in multiple immune functions, therapies targeting S1P axis may be applicable to treat autoimmune diseases other than MS. Currently, over a dozen selective S1PR and S1P pathway modulators with potentially superior therapeutic efficacy and better side-effect profiles are in the pipeline of drug development. Furthermore, newly characterized molecules such as apolipoprotein M (ApoM) (S1P chaperon) and SPNS2 (S1P transporter) are also potential targets for treatment of autoimmune diseases. Finally, the application of therapies targeting S1P and S1P signaling pathways may be expanded to treat several other immune-mediated disorders (such as post-infectious diseases, post-stroke and post-stroke dementia) and inflammatory conditions beyond their application in primary autoimmune diseases.
View details for DOI 10.1007/s40265-016-0603-2
View details for Web of Science ID 000379497000001
View details for PubMedID 27318702
Mechanisms of Cholera Toxin in the Modulation of TH17 Responses.
Critical reviews in immunology
2015; 35 (2): 135-152
Fingolimod (FTY720, Gilenya), a sphingosine-1-phosphate receptor (S1PR) modulator, is one of the first-line immunomodulatory therapies for treatment of relapsing-remitting multiple sclerosis (MS). Human S1PR1 variants have been reported to have functional heterogeneity in vitro, suggesting that S1PR1 function may influence FTY720 efficacy. In this study, we examined the influence of S1PR1 phosphorylation on response to FTY720 in neuroinflammation. We found that mice carrying a phosphorylation-defective S1pr1 gene [S1PR1(S5A) mice] were refractory to FTY720 treatment in MOG35-55-immunized and Th17-mediated experimental autoimmune encephalomyelitis (EAE) models. Long-term treatment with FTY720 induced significant lymphopenia and suppressed Th17 response in the peripheral immune system via downregulating STAT3 phosphorylation in both WT and S1PR1(S5A) mice. However, FTY720 did not effectively prevent neuroinflammation in the S1PR1(S5A) EAE mice as a result of encephalitogenic cells expressing C-C chemokine receptor 6 (CCR6). Combined treatment with FTY720 and anti-CCR6 delayed disease progression in S1PR1(S5A) EAE mice, suggesting that CCR6-mediated cell trafficking can overcome the effects of FTY720. This work may have translational relevance regarding FTY720 efficacy in MS patients and suggests that cell type-specific therapies may enhance therapeutic efficacy in MS.
View details for PubMedID 27699272
View details for PubMedCentralID PMC5033897
Cholera Toxin Directly Enhances IL-17A Production from Human CD4(+) T Cells
JOURNAL OF IMMUNOLOGY
2013; 191 (8): 4095-4102
Numerous studies have shown that TH17 cells and their signature cytokine IL-17A are critical to host defense against various bacterial and fungal infections. The protective responses mediated by TH17 cells and IL-17A include the recruitment of neutrophils, release of antimicrobial peptides and chemokines, and enhanced tight junction of epithelial cells. Due to the importance of TH17 cells in infections, efforts have been made to develop TH17-based vaccines. The goal of vaccination is to establish a protective immunological memory. Most currently approved vaccines are antibody-based and have limited protection against stereotypically different strains. Studies show that T-cell-based vaccines may overcome this limitation and protect hosts against infection of different strains. Two main strategies are used to develop TH17 vaccines: identification of TH17-specific antigens and TH17-skewing adjuvants. Studies have revealed that cholera toxin (CT) induces a potent Th17 response following vaccination. Antigen vaccination along with CT induces a robust TH17 response, which is sometimes accompanied by TH1 responses. Due to the toxicity of CT, it is hard to apply CT in a clinical setting. Thus, understanding how CT modulates TH17 responses may lead to the development of successful TH17-based vaccines.
View details for PubMedID 26351147
IL-17A and Th17 Cells in Lung Inflammation: An Update on the Role of Th17 Cell Differentiation and IL-17R Signaling in Host Defense against Infection
CLINICAL & DEVELOPMENTAL IMMUNOLOGY
The significance of Th17 cells and IL-17A signaling in host defense and disease development has been demonstrated in various infection and autoimmune models. Additionally, the generation of Th17 cells is highly influenced by microbes. However, the specific bacterial components capable of shaping Th17 responses have not been well defined. The goals of this study were to understand how a bacterial toxin, cholera toxin (CT), modulates Th17-dominated response in isolated human CD4(+) T cells, and what are the mechanisms associated with this modulation. CD4(+) cells isolated from human peripheral blood were treated with CT. The levels of cytokine production and specific Th cell responses were determined by ELISA, Luminex assay, and flow cytometry. Along with the decreased production of other proinflammatory cytokines (IFN-?, TNF-?, and IL-2), we found that CT could directly enhance the IL-17A production through a cAMP-dependent pathway. This enhancement is specific for IL-17A but not for IL-17F, IL-22, and CCL20. Interestingly, CT could increase IL-17A production only from Th17-committed cells, such as CCR6(+)CD4(+) T cells and in vitro-differentiated Th17 cells. Furthermore, we also demonstrated that this direct effect occurs at a transcriptional level because CT stimulates the reporter activity in Jurkat and primary CD4(+) T cells transfected with the IL-17A promoter-reporter construct. This study shows that CT has the capacity to directly shape Th17 responses in the absence of APCs. Our findings highlight the potentials of bacterial toxins in the regulation of human Th17 responses.
View details for DOI 10.4049/jimmunol.1301079
View details for Web of Science ID 000325487700016
View details for PubMedID 24043897
The significance of Th17 cells and interleukin- (IL-)17A signaling in host defense and disease development has been demonstrated in various infection and autoimmune models. Numerous studies have indicated that Th17 cells and its signature cytokine IL-17A are critical to the airway's immune response against various bacteria and fungal infection. Cytokines such as IL-23, which are involved in Th17 differentiation, play a critical role in controlling Klebsiella pneumonia (K. pneumonia) infection. IL-17A acts on nonimmune cells in infected tissues to strengthen innate immunity by inducing the expression of antimicrobial proteins, cytokines, and chemokines. Mice deficient in IL-17 receptor (IL-17R) expression are susceptible to infection by various pathogens. In this review, we summarize the recent advances in unraveling the mechanism behind Th17 cell differentiation, IL-17A/IL-17R signaling, and also the importance of IL-17A in pulmonary infection.
View details for DOI 10.1155/2013/267971
View details for Web of Science ID 000322464600001
View details for PubMedID 23956759