MIF Promotes Classical Activation and Conversion of Inflammatory Ly6C<sup>high</sup>Monocytes into TipDCs during Murine Toxoplasmosis

Ruíz-Rosado, Juan de Dios; Juárez-Avelar, Imelda; Saavedra, Rafael; Terrazas, Luis I.; Robledo‐Avila, Frank; Vázquez-Mendoza, Alicia; Fernández, Jacquelina; Satoskar, Abhay R.; Partida-Sánchez, Santiago; Rodrı́guez-Sosa, Miriam

doi:10.1155/2016/9101762

Cited by 24 publications

(20 citation statements)

References 57 publications

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“…Nevertheless, additional studies are needed to more precisely clarify the roles of MIF and D-DT in MS, especially with respect to the mechanistic role of their common receptor CD74 and that of the noncognate chemokine receptors CXCR2 and CXCR4 (9). Furthermore, it would be interesting to evaluate whether increased MIF and D-DT levels in MS might promote the activation of Ly6C hi inflammatory monocytes similar to their effects described in parasite infections (55).…”

Section: Discussionmentioning

confidence: 99%

MIF and D-DT are potential disease severity modifiers in male MS subjects

Benedek

Meza-Romero

Jordan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Little is known about mechanisms that drive the development of progressive multiple sclerosis (MS), although inflammatory factors, such as macrophage migration inhibitory factor (MIF), its homolog D-dopachrome tautomerase (D-DT), and their common receptor CD74 may contribute to disease worsening. Our findings demonstrate elevated MIF and D-DT levels in males with progressive disease compared with relapsing-remitting males (RRMS) and female MS subjects, with increased levels of CD74 in females vs. males with high MS disease severity. Furthermore, increased MIF and D-DT levels in males with progressive disease were significantly correlated with the presence of two high-expression promoter polymorphisms located in the gene, a -794CATT microsatellite repeat and a -173 G/C SNP. Conversely, mice lacking MIF or D-DT developed less-severe signs of experimental autoimmune encephalomyelitis, a murine model of MS, thus implicating both homologs as copathogenic contributors. These findings indicate that genetically controlled high MIF expression (and D-DT) promotes MS progression in males, suggesting that these two factors are sex-specific disease modifiers and raising the possibility that aggressive anti-MIF treatment of clinically isolated syndrome or RRMS males with a high-expresser genotype might slow or prevent the onset of progressive MS. Additionally, selective targeting of MIF:CD74 signaling might provide an effective, trackable therapeutic approach for MS subjects of both sexes.

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Section: Discussionmentioning

confidence: 99%

MIF and D-DT are potential disease severity modifiers in male MS subjects

Benedek

Meza-Romero

Jordan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, it has been proposed that DC orchestrate the autoimmune response in T1DM via TLR-2 and TLR-4 [ 58 ]. Previous studies by us and others have shown that Mif induces the expression of costimulatory molecules on M φ and DC in some pathological infections [ 59 – 61 ]. Here, we identified the expression of costimulatory molecules and TLR-2 and TLR-4 on M φ and DC, as well as the ability of M φ to activate T lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Altered Macrophage and Dendritic Cell Response inMif−/− Mice Reveals a Role of Mif for Inflammatory-Th1 Response in Type 1 Diabetes

Juárez-Avelar

Vázquez-Mendoza

Hiriart

et al. 2016

Journal of Diabetes Research

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Macrophage migration inhibitory factor (Mif) is highly expressed in type 1 diabetes mellitus (T1DM). However, there is limited information about how Mif influences the activation of macrophages (Mφ) and dendritic cells (DC) in T1DM. To address this issue, we induced T1DM by administering multiple low doses of streptozotocin (STZ) to Mif−/− or wild-type (Wt) BALB/c mice. We found that Mif−/− mice treated with STZ (Mif−/−STZ) developed lower levels of hyperglycemia, inflammatory cytokines, and specific pancreatic islet antigen- (PIAg-) IgG and displayed reduced cellular infiltration into the pancreatic islets compared to Wt mice treated with STZ (WtSTZ). Moreover, Mφ and DC from Mif−/−STZ displayed lower expression of MHC-II, costimulatory molecules CD80, CD86, and CD40, Toll-like receptor- (TLR-) 2, and TLR-4 than WtSTZ. These changes were associated with a reduced capacity of Mφ and DC from Mif−/−STZ to induce proliferation in ovalbumin-specific T cells. All the deficiencies observed in Mif−/−STZ were recovered by exogenous administration of recombinant Mif. These findings suggest that Mif plays a role in the molecular mechanisms of Mφ and DC activation and drives T cell responses involved in the pathology of T1DM. Therefore, Mif is a potential therapeutic target to reduce the pathology of T1DM.

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“…However, the previous studies showed that MIF reduced the Toxoplasma infection in in vivo and in vitro experimental models. One group demonstrated that MIF promotes the classical activation of monocytes, promoting resistance to T. gondii infection in MIF −/− mice treated with recombinant MIF (Ruiz-Rosado et al., 2016). Another study using T. gondii -infected MIF −/− mice showed reduced lethality, as well as ileum inflammation and tissue damage, despite increased parasite intestinal load in relation to wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

Increased Toxoplasma gondii Intracellular Proliferation in Human Extravillous Trophoblast Cells (HTR8/SVneo Line) Is Sequentially Triggered by MIF, ERK1/2, and COX-2

et al. 2019

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Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine, which mediates the regulation of diverse cellular functions. It is produced by extravillous trophoblastic cells and has been found to be involved in the pathogenesis of diseases caused by some protozoa, including Toxoplasma gondii . Previous studies demonstrated the ability of T. gondii to take advantage of MIF action in human trophoblast cells. However, MIF action in T. gondii -infected extravillous trophoblastic cells (HTR8/SVneo cell line) has not been fully investigated. The present study aimed to investigate the role of MIF in T. gondii -infected HTR8/SVneo cells and verify the intracellular signaling pathways triggered by this cytokine. We found that T. gondii increased MIF production by HTR8/SVneo cells, and by contrast, MIF inhibition, by ISO-1, led to a significant decrease in T. gondii proliferation and CD74 expression in HTR8/SVneo cells. Moreover, in infected HTR8/SVneo cells, the addition of recombinant MIF (rMIF) increased CD44 co-receptor expression, ERK1/2 phosphorylation, COX-2 expression, and IL-8 production, which favored T. gondii proliferation. Our findings indicate that T. gondii can use MIF to modulate important factors in HTR8/SVneo cells, being a possible explanation for the higher susceptibility of extravillous trophoblast cells than other trophoblast cell populations.

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MIF Promotes Classical Activation and Conversion of Inflammatory Ly6C^highMonocytes into TipDCs during Murine Toxoplasmosis

Cited by 24 publications

References 57 publications

MIF and D-DT are potential disease severity modifiers in male MS subjects

MIF and D-DT are potential disease severity modifiers in male MS subjects

Altered Macrophage and Dendritic Cell Response inMif−/− Mice Reveals a Role of Mif for Inflammatory-Th1 Response in Type 1 Diabetes

Increased Toxoplasma gondii Intracellular Proliferation in Human Extravillous Trophoblast Cells (HTR8/SVneo Line) Is Sequentially Triggered by MIF, ERK1/2, and COX-2

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MIF Promotes Classical Activation and Conversion of Inflammatory Ly6ChighMonocytes into TipDCs during Murine Toxoplasmosis

Cited by 24 publications

References 57 publications

MIF and D-DT are potential disease severity modifiers in male MS subjects

MIF and D-DT are potential disease severity modifiers in male MS subjects

Altered Macrophage and Dendritic Cell Response inMif−/− Mice Reveals a Role of Mif for Inflammatory-Th1 Response in Type 1 Diabetes

Increased Toxoplasma gondii Intracellular Proliferation in Human Extravillous Trophoblast Cells (HTR8/SVneo Line) Is Sequentially Triggered by MIF, ERK1/2, and COX-2

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MIF Promotes Classical Activation and Conversion of Inflammatory Ly6C^highMonocytes into TipDCs during Murine Toxoplasmosis