The mast cell/S1P axis is not linked to pre-lesional male skin remodeling in a mouse model of eczema

Abstract

<abstract> <p>Atopic dermatitis (AD, eczema) is an inflammatory skin condition whose histopathology involves remodeling. Few preclinical AD studies are performed using male mice. The histopathological mechanisms underlying AD development were investigated here in male mice at a pre-lesional stage using a human AD-like mouse model. Hypodermal cellular infiltration without thickening of skin layers was observed after one epicutaneous exposure to antigen ovalbumin (OVA), compared to controls. In contrast to our previous report using female mice, OVA treatment did not activate skin mast cells (MC) or elevate sphingosine-1-phosphate (S1P) levels while increasing systemic but not local levels of CCL2, CCL3 and CCL5 chemokines. In contrast to the pathogenic AD mechanisms we recently uncovered in female, S1P-mediated skin MC activation with subsequent local chemokine production is not observed in male mice, supporting sex differences in pre-lesional stages of AD. We are proposing that differential involvement of the MC/S1P axis in early pathogenic skin changes contributes to the well documented yet still incompletely understood sex-dimorphic susceptibility to AD in humans.</p> </abstract>

Resveratrol Protects against Skin Inflammation through Inhibition of Mast Cell, Sphingosine Kinase-1, Stat3 and NF-κB p65 Signaling Activation in Mice

“…We previously reported that one week of exposure to O triggered significant infiltration of cells in the hypodermis, compared to saline controls, in a mouse model of AD, including around blood vessels (BV) [ 16 , 17 ]. We applied the computer-assisted cell quantification method described previously [ 16 , 17 ] to measure cell infiltration in the entire hypodermis, as well as around BV ( Figure 3 ).…”

“…We previously established a new morphometric imaging method to quantify mammal mast cells (MCs) and MC activation status in microscopy slides [ 16 , 17 ]. In situ quantifications were conducted in differentially treated mouse skins using our computer-aided method to identify MCs ( Figure 4 a) and distinguish resting from activated (degranulated) MCs ( Figure 4 b).…”

“…Previously published studies demonstrated that one-week exposure to O induces increased chemokines CCL2 , CCL3 , and CCL5 skin mRNA levels in female [ 16 ] but not in male mice [ 17 ]. In the current study, mRNA expression levels featured a similar elevation upon O application and were normalized in skin samples exposed to O and resveratrol for 7 days ( Figure 5 a,c), except for CCL3 chemokine ( Figure 5 b).…”

“…We show that resveratrol potently inhibits multiple features of the patho-mechanistic events occurring at the onset of AD. Thus, epidermal thickening that was observed in early-phase AD was prevented by R treatment in a well-established human-like mouse model utilizing the epicutaneous application of antigen O on the dorsal skin [ 16 , 17 , 33 , 34 ]. Importantly, we used our established expertise in quantitative imaging [ 16 , 17 , 18 , 35 ] to develop a new computer-assisted method extensively described herein, to measure skin layer thickness.…”

“…Mast cells are skin-resident innate immune cells that initiate many aspects of inflammatory responses due to strategic tissue residence in close proximity to blood vessels and have a unique ability to synthesize and store an arsenal of bioactive substances [ 11 , 12 , 13 ]. Released upon activation, a process also named degranulation, MC mediators regulate inflammation by recruiting cells from the circulation, as well as acting on neighboring cells to orchestrate tissue remodeling [ 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. We have previously reported inflammation-enabling functions of bioactive sphingolipid sphingosine-1-phosphate (S1P)-activated MCs in early-phase AD in mice, suggesting that controlling MC reactivity may prevent the development of AD [ 16 , 18 ].…”