Available online 11 June 2022, 104561

MIF-1 contribution to severe acute EAE was stronger in females than in males.

DRa1-MOG-35-55 treatment of MIF-1-KO mice resulted in a “near cure” in both sexes.

Improved clinical scores were mirrored by reduced chemokine expression patterns.

Our previous studies demonstrated increased serum levels of macrophage migration inhibitory factor (MIF-1) and its homologue, MIF-2, in males during MS progression; and that genetically high-MIF-expressing male subjects with relapsing multiple sclerosis (MS) had a significantly greater risk of conversion to progressive MS than lower-MIF-expressing males and females. However, female MS subjects with severe disease expressed higher levels of CD74, the common MIF-1/MIF-2 receptor, on blood cells. In the murine model of MS, experimental autoimmune encephalomyelitis (EAE), both male and female mice lacking MIF-1 and/or MIF-2 were clinically improved during development of moderately severe disease, thus implicating both homologs as co-pathogenic contributors. The current study using MIF-deficient mice with severe acute EAE revealed a highly significant reduction of EAE scores in MIF-1-deficient females, in contrast to only minor and delayed reduction of clinical signs in MIF-1-deficient males. However, clinical EAE scores and factor expression were strongly suppressed in males and further reduced in females after treatment of WT and MIF-1-, MIF-2- and MIF-1/2-DUAL-deficient female and male mice with a MHCII DRα1-MOG-35-55 molecular construct that competitively inhibits MIF-1 & MIF-2 signaling through CD74 as well as T cell activation. These results suggest sex-dependent differences in which the absence of the MIF-1 and/or MIF-2 genotypes may permit stronger compensatory CD74-dependent EAE-inducing responses in males than in females. However, EAE severity in both sexes could still be reduced nearly to background (a “near cure”) with DRα1-MOG-35-55 blockade of compensatory MIF and CD74-dependent factors known to attract peripheral inflammatory cells into the spinal cord tissue.

Multiple sclerosis (MS)

experimental autoimmune encephalomyelitis (EAE)

sex differences

inflammation

cytokines/chemokines

central nervous system (CNS)

macrophage migration inhibitory factors (MIF-1 & MIF-2)

DRα1-MOG-35-55 construct, CD74

wild type mouse strain

Complementary deoxynucleic acid

Cumulative Disease Index

Central Nervous System

Complete Freund’s adjuvant

DRα1-MOG-35-55

Experimental autoimmune encephalomyelitis

Major histocompatibility complex

Mycobacterium tuberculosis

Myelin oligodendrocyte glycoprotein 35-55

Phosphate-buffered saline

Standard error of the mean

© 2022 Published by Elsevier Inc.