title: Leukotriene B₄-leukotriene B₄ receptor axis promotes oxazolone-induced contact dermatitis by directing skin homing of neutrophils and CD8⁺ T cells.
abstract: Leukotriene B4 (LTB4 ) is a lipid mediator that is rapidly generated in inflammatory sites, and its functional receptor, BLT1, is mostly expressed on immune cells. Contact dermatitis is a common inflammatory skin disease characterized by skin oedema and abundant inflammatory infiltrates, primarily including neutrophils and CD8(+) T cells. The role of the LTB4 -BLT1 axis in contact dermatitis remains largely unknown. In this study, we found up-regulated gene expression of 5-lipoxygenase and leukotriene A4 hydrolase, two critical enzymes for LTB4 synthesis, BLT1 and elevated LTB4 levels in skin lesions of oxazolone (OXA)-induced contact dermatitis. BLT1 deficiency or blockade of LTB4 and BLT1 by the antagonists, bestatin and U-75302, respectively, in the elicitation phase caused significant decreases in ear swelling and skin-infiltrating neutrophils and CD8(+) T cells, which was accompanied by significantly reduced skin expression of CXCL1, CXCL2, interferon-γ and interleukin-1β. Furthermore, neutrophil depletion during the elicitation phase of OXA-induced contact dermatitis also caused significant decreases in ear swelling and CD8(+) T-cell infiltration accompanied by significantly decreased LTB4 synthesis and gene expression of CXCL2, interferon-γ and interleukin-1β. Importantly, subcutaneous injection of exogenous LTB4 restored the skin infiltration of CD8(+) T cells in neutrophil-depleted mice following OXA challenge. Collectively, our results demonstrate that the LTB4 -BLT1 axis contributes to OXA-induced contact dermatitis by mediating skin recruitment of neutrophils, which are a major source of LTB4 that sequentially direct CD8(+) T-cell homing to OXA-challenged skin. Hence, LTB4 and BLT1 could be potential therapeutic targets for the treatment of contact dermatitis.
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Jiaoyan
authors.initials: J
authors.lastname: Lv
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Zou
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Yingluo
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Bingji
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.|Biotherapy Research Centre, Fudan University, Shanghai, China.
authors.forename: Rui
authors.initials: R
authors.lastname: He
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D003877:Dermatitis, Contact / Q000188:drug therapy / Q000276:immunology*; D004851:Epoxide Hydrolases / Q000096:biosynthesis; D005233:Fatty Alcohols / Q000494:pharmacology; D005260:Female; D006018:Glycols / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D010081:Oxazolone; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D012867:Skin / Q000166:cytology / Q000276:immunology
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D005233:Fatty Alcohols; D006018:Glycols; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; C503704:Ltb4r1 protein, mouse; D018102:Receptors, Leukotriene B4; C062137:U 75302; D010081:Oxazolone; D007975:Leukotriene B4; D007371:Interferon-gamma; D001094:Arachidonate 5-Lipoxygenase; D004851:Epoxide Hydrolases; D007930:Leucine; C012211:ubenimex; C043134:leukotriene A4 hydrolase
keywords: CD8 T cells; elicitation phase of contact dermatitis; leukotriene B4-BLT1 axis; neutrophils; skin homing