The multifaced role of the macrophage migration inhibitory factor family in organ fibrosis

Abstract

The macrophage migration inhibitory factor (MIF) family consists of the structurally homologous proteins MIF, D-dopachrome tautomerase (D-DT), and D-DT like (D-DTL). Although MIF is the most well-described member, much less is known about D-DT, and very little about D-DTL. Here, we provide an overview of the structure, similarities, and biological functions of these proteins. MIF and D-DT can have both protective and aggravating effects on various diseases depending on the disease type, involved organ, cell type, and disease stage. Given that the pathological consequence of many chronic diseases is fibrosis, we here discuss the role of these proteins in organ fibrosis, particularly of the kidney, liver, heart, lung, and skin. We discuss the various roles of these proteins, suggesting that MIF might have pro- and antifibrotic roles in different organs. To date, D-DT has been shown to have only antifibrotic roles. We tackle potential translational considerations and propose future research avenues to better understand the involvement of MIF family in organ fibrosis.

Keywords: CD74; D-DT; D-DTL; clinical trials.

Figure 1. Overview of the MIF-family.

The overview includes the properties of the proteins macrophage migration inhibitors factor (MIF), D-dopachrome tautomerase (D-DT) and D-DT like (D-DTL) in the category: gene, structure, receptors, and CD74 binding. Due to the limited data available on D-DTL, unknown properties are marked with a question mark. Created in BioRender. Boor, P. (2025) https://BioRender.com/q16n769.

Figure 2. RNA and protein expression comparison of the MIF-family, and CD74.

(A) In a heat map, the RNA expression of MIF, D-DT, D-DTL, and CD74 was screened in different tissues. The RNA-seq tissue data generated as part of the Genotype-Tissue Expression (GTEx) project are indicated as nTPM (normalized protein-coding transcripts per million), corresponding to the mean values of the various individual samples from each tissue. The nTPM values got normalized for each organ. (B) MIF, D-DT, and CD74 protein expression were compared in immunohistochemistry staining of the kidney, liver, heart, lung, and skin. D-DTL was excluded because of insufficient staining. Scalebar: 50 μm. The RNA and protein data are sourced from the Human Protein Atlas (72). Image/gene/data available from v24.0.proteinatlas.org. Created in BioRender. Boor, P. (2025) https://BioRender.com/w32f754.

Figure 3. Expression of the MIF-family and CD74 of the respective cell types in different tissues.

The data originates from single-cell RNA analyses. RNA expression of each cluster is indicated as nTPM (normalized protein-coding transcripts per million) from each cell type from the kidney, liver, heart, lung, and skin. The single-cell RNA sequencing data are sourced from the Human Protein Atlas (72). Data are available from v24.0.proteinatlas.org. The cluster data was summarized by taking the mean value of the same cell types. Created in BioRender. Boor, P. (2025) https://BioRender.com/3h6zrcy.