Topical Application of Fingolimod Perturbs Cutaneous Inflammation

Abstract

The prevalence of allergies, including rhinitis, eczema, and anaphylaxis, is rising dramatically worldwide. This increase is especially problematic in children who bear the greatest burden of this rising trend. Increasing evidence identifies neutrophils as primary perpetrators of the more severe and difficult to manage forms of inflammation. A newly recognized mechanism by which neutrophils are recruited during the early phase of histamine-induced inflammation involves the sphingosine kinase (SK)/sphingosine-1-phosphate axis. This study examines whether topical application of fingolimod, an established SK/sphingosine-1-phosphate antagonist already in clinical use to treat multiple sclerosis, may be repurposed to treat cutaneous inflammation. Using two mouse models of ear skin inflammation (histamine- and IgE-mediated passive cutaneous anaphylaxis) we topically applied fingolimod prophylactically, as well as after establishment of the inflammatory response, and examined ear swelling, SK activity, vascular permeability, leukocyte recruitment, and production of proinflammatory mediators. The present study reveals that when applied topically, fingolimod attenuates both immediate and late-phase responses to histamine with reduced extravasation of fluid, SK-1 activity, proinflammatory cytokine and chemokine production, and neutrophil influx and prevents ear swelling. Intravital microscopy demonstrates that histamine-induced neutrophil rolling and adhesion to the postcapillary venules in the mouse ears is significantly attenuated even after 24 h. More importantly, these effects are achievable even once inflammation is established. Translation into humans was also accomplished with epicutaneous application of fingolimod resolving histamine-induced and allergen-induced inflammatory reactions in forearm skin. Overall, this study demonstrates, to our knowledge for the first time, that fingolimod may be repurposed to treat cutaneous inflammation.

Mast cells and sphingosine‐1‐phosphate underlie prelesional remodeling in a mouse model of eczema

“…Topical application of fingolimod (FTY720), a structural analog of sphingosine also phosphorylated by SphK, acts as an S1P receptor (R) agonist and attenuates skin inflammation . FTY720 treatment prevented enhanced MC degranulation after OVA treatment (Figure A).…”

Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis

“…Depletion of peripheral leukocytes in this model could explain the decreased migration of neutrophils (Czech et al, 2009). However, the precise mechanism by which FTY720 regulates neutrophil migration in this and other in vivo studies is largely unknown and awaits further investigation (Finley et al, 2013; Sun et al, 2016). The cumulative data does suggest that S1P signaling is altering multiple aspects of neutrophil biology, possibly in a tissue specific manner, and thus conditional KO models would be useful to characterize these pathways.…”

Sphingosine‐1‐phosphate modulators in inflammatory skin diseases – lining up for clinical translation

“…In histamine‐induced skin inflammation, topically applied fingolimod significantly attenuated early‐ and late‐phase skin inflammation in mice by reducing extravasation of fluid, cytokine and chemokine expression as well as neutrophil recruitment into the skin . Likewise, in human skin, topical treatment with fingolimod ameliorated wheals induced by epicutaneously applied histamine or allergens . Systemic application of fingolimod also completely protected NC/Nga mice from spontaneous atopic dermatitis‐like skin inflammation .…”

“…The role of S1P in the pathogenesis of allergic skin inflammation has been examined in several mouse models representing different subtypes of allergic skin inflammation, including atopic dermatitis‐like spontaneous skin inflammation of NC/Nga mice, histamine‐induced skin inflammation and hapten‐induced skin hypersensitivity. In histamine‐induced skin inflammation, topically applied fingolimod significantly attenuated early‐ and late‐phase skin inflammation in mice by reducing extravasation of fluid, cytokine and chemokine expression as well as neutrophil recruitment into the skin . Likewise, in human skin, topical treatment with fingolimod ameliorated wheals induced by epicutaneously applied histamine or allergens .…”

“…With no significant difference in the efficiency of 20 and 40 mg ponesimod to clear psoriatic plaques, it is conceivable that lower doses of ponesimod are still effective but cause less side effects . In addition, as topical application of S1P receptor modulators has been effective in several mouse models of dermatitis, topical application of ponesimod or other functional antagonists of S1P 1 should be examined to exploit the proven therapeutic potential of the S1P system in the treatment of psoriasis. Notably, another S1P1 agonist, topical AKP‐11, is currently investigated as therapeutic in atopic dermatitis and plaque psoriasis in phase I and II clinical trials http://www.australianclinicaltrials.gov.au.…”