Sphingolipids Are Dual Specific Drug Targets for the Management of Pulmonary Infections: Perspective - PubMed (original) (raw)
Review
Sphingolipids Are Dual Specific Drug Targets for the Management of Pulmonary Infections: Perspective
Lalita Sharma et al. Front Immunol. 2017.
Abstract
Sphingolipids are the major constituent of the mucus secreted by the cells of epithelial linings of lungs where they maintain the barrier functions and prevent microbial invasion. Sphingolipids are interconvertible, and their primary and secondary metabolites have both structural and functional roles. Out of several sphingolipid metabolites, sphingosine-1 phosphate (S1P) and ceramide are central molecules and decisive for sphingolipid signaling. These are produced by enzymatic activity of sphingosine kinase-1 (SK-1) upon the challenge with either biological or physiological stresses. S1P and ceramide rheostat are important for the progression of various pathologies, which are manifested by inflammatory cascade. S1P is a well-established secondary messenger and associated with various neuronal, metabolic, and inflammatory diseases other than respiratory infections such as Chlamydia pneumoniae, Streptococcus pneumoniae, and Mycobacterium tuberculosis. These pathogens are known to exploit sphingolipid metabolism for their opportunistic survival. Decreased sphingosine kinase activity/S1P content in the lung and peripheral blood of tuberculosis patients clearly indicated a dysregulation of sphingolipid metabolism during infection and suggest that sphingolipid metabolism is important for management of infection by the host. Our previous study has demonstrated that gain of SK-1 activity is important for the maturation of phagolysosomal compartment, innate activation of macrophages, and subsequent control of mycobacterial replication/growth in macrophages. Furthermore, S1P-mediated amelioration of lung pathology and disease severity in TB patients is believed to be mediated by the selective activation or rearrangement of various S1P receptors (S1PR) particularly S1PR2, which has been effective in controlling respiratory fungal pathogens. Therefore, such specificity of S1P-S1PR would be paramount for triggering inflammatory events, subsequent activation, and fostering bactericidal potential in macrophages for the control of TB. In this review, we have discussed and emphasized that sphingolipids may represent effective novel, yet dual specific drug targets for controlling pulmonary infections.
Keywords: ceramide; lungs; macrophages; microbes; sphingolipids; sphingosine kinase-1.
Figures
Figure 1
Pathway for synthesis of ceramide, sphingomyelin, and sphingosine-1 phosphate. (A) The de novo synthesis of ceramide starts with palmitoyl-CoA and serine in endoplasmic reticulum. Ceramide is then converted to sphingomyelin, which is the structural component of outer leaflet of plasma membrane. (B) Enhanced ceramide concentration in lungs results in inflammation and cell damage therefore dynamic balance of sphingosine/S1P/ceramide is important for pathological manifestation during TB infection.
Figure 2
Sphingolipids (S1P) mediate protective inflammatory response during infection. Certain environmental stress such as air pollution and respiratory diseases caused by genetic alterations (cystic fibrosis) led to an increase in sialylated glycosphingolipid content in epithelial cell lining of lungs, which serve as receptors for many bacteria (Mycoplasma pneumonia and Pseudomonas aeruginosa). Mycobacterium tuberculosis inhibits the activity of sphingosine kinase in macrophages, which results in decreased intracellular concentration of Ca2+ ions and subsequent phagosome maturation arrest that can be modulated by selective upregulation of S1PR2-associated antimicrobial signaling in the alveolar macrophages.
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