Sphingosine-1-Phosphate (S-1P) Promotes Differentiation of Naive Macrophages and Enhances Protective Immunity Against Mycobacterium tuberculosis

Abstract

Sphingosine-1-phosphate (S-1P) is a key sphingolipid involved in the pathobiology of various respiratory diseases. We have previously demonstrated the significance of S-1P in controlling non-pathogenic mycobacterial infection in macrophages, and here we demonstrate the therapeutic potential of S-1P against pathogenic Mycobacterium tuberculosis (H37Rv) in the mouse model of infection. Our study revealed that S-1P is involved in the expression of iNOS proteins in macrophages, their polarization toward M1 phenotype, and secretion of interferon (IFN)-γ during the course of infection. S-1P is also capable of enhancing infiltration of pulmonary CD11b+ macrophages and expression of S-1P receptor-3 (S-1PR3) in the lungs during the course of infection. We further revealed the influence of S-1P on major signaling components of inflammatory signaling pathways during M. tuberculosis infection, thus highlighting antimycobacterial potential of S-1P in animals. Our data suggest that enhancing S-1P levels by sphingolipid mimetic compounds/drugs can be used as an immunoadjuvant for boosting immunity against pathogenic mycobacteria.

Tempering Macrophage Plasticity for Controlling SARS-CoV-2 Infection for Managing COVID-19 Disease

“…Apart from these, we have validated several other immune adjuvants, such as low dose Gamma Radiation (Klug et al, 2013;Prakash et al, 2016), S-1P (Nadella et al, 2019), and Smac mimetics (Nadella et al, 2017), which indicate the potential of the Th1 programming of macrophages in a pre-clinical model system. These adjuvants are likely to create immunity against SARS-CoV-2 infection in the animal models discussed above.…”

Macrophage plasticity as a therapeutic target in tuberculosis

“…Treatment of H37Rv‐infected RAW 264.7 macrophages and bone marrow‐derived macrophages with sphingosine‐1‐phosphate (S1P), a bioactive lipid, differentiate resting macrophage into M1 polarized macrophages, reflected by an increase in NO and IFN‐γ production. The study further showed the S1P treatment significantly rescued macrophages from the infection [56]. Similarly, in a recent study, treatment with rocaglates, a natural compound isolated from Aglaia species, contributes to inhibition of Erk‐dependent M2 polarization with concomitantly increased response to IFNγ via p38 activation.…”

Host sphingolipids: Perspective immune adjuvant for controlling SARS-CoV-2 infection for managing COVID-19 disease

“…Moreover, S1PR1 signaling is known to activate Ras, MAPK, PI3K/AKT, and mTOR pathways, which drive substantial Th2 / 17 responses [ 23 ] hypoxia, allergic manifestations [ 26 ] and aberrant pathology which are anticipated to promote replication of SARS-CoV-2 infection and would account for novel COVID-19 related death. Given S1P related pathogenic inflammation and association of S1PR1 and ACE2 linked signaling, it is likely that S1P, despite its antibacterial potential [ 29 ], might not be effective in controlling SARS-CoV-2 infection. Hence blocking S1P response either by enhancing S1P lyase activity [ 30 ] or inhibiting its binding to its receptor by use of analogue known as FTY720 (Fingolimod) [ 31 , 32 ] may modulate the pathogenesis of novel COVID-19 cases.…”