title: A small-molecule macrophage migration inhibitory factor antagonist protects against glomerulonephritis in lupus-prone NZB/NZW F1 and MRL/lpr mice.
abstract: Autoimmunity leads to the activation of innate effector pathways, proinflammatory cytokine production, and end-organ injury. Macrophage migration inhibitory factor (MIF) is an upstream activator of the innate response that mediates the recruitment and retention of monocytes via CD74 and associated chemokine receptors, and it has a role in the maintenance of B lymphocytes. High-expression MIF alleles also are associated with end-organ damage in different autoimmune diseases. We assessed the therapeutic efficacy of (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), an orally bioavailable MIF antagonist, in two distinct models of systemic lupus erythematosus: the NZB/NZW F1 and the MRL/lpr mouse strains. ISO-1, like anti-MIF, inhibited the interaction between MIF and its receptor, CD74, and in each model of disease, it reduced functional and histological indices of glomerulonephritis, CD74(+) and CXCR4(+) leukocyte recruitment, and proinflammatory cytokine and chemokine expression. Neither autoantibody production nor T and B cell activation were significantly affected, pointing to the specificity of MIF antagonism in reducing excessive proinflammatory responses. These data highlight the feasibility of targeting the MIF-MIF receptor interaction by small-molecule antagonism and support the therapeutic value of downregulating MIF-dependent pathways of tissue damage in systemic lupus erythematosus.
authors.affiliation: Department of Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Juan
authors.initials: J
authors.lastname: Fan
authors.forename: Dorothee
authors.initials: D
authors.lastname: Greven
authors.forename: Alvaro
authors.initials: A
authors.lastname: Arjona
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.forename: David
authors.initials: D
authors.lastname: Austin
authors.forename: Michael
authors.initials: M
authors.lastname: Kashgarian
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Yin
authors.forename: Xiao R
authors.initials: XR
authors.lastname: Huang
authors.forename: Hui Y
authors.initials: HY
authors.lastname: Lan
authors.forename: Elias
authors.initials: E
authors.lastname: Lolis
authors.forename: David
authors.initials: D
authors.lastname: Nikolic-Paterson
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002464:Cell Migration Inhibition / Q000187:drug effects / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007555:Isoxazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011897:Random Allocation; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D011971:Receptors, Immunologic; C033184:macrophage migration inhibitory factor receptor; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse