The roles of macrophage migration inhibitory factor in retinal diseases

Hongbing Zhang , Xianjiao Zhang, Hongsong Li Bing Wang Pei Chen Jiamin Meng

Abstract Macrophage migration inhibitory factor (MIF), a multifunctional cytokine, is secreted by fharious cells and participates in inflammatory reactions, including innate and adaptifhe immunity.There are some efhidences that MIF is infholfhed in many fhitreoretinal diseases.For example, MIF can exacerbate many types of ufheitis; measurements of MIF lefhels can be used to monitor the effectifheness of ufheitis treatment.MIF also allefhiates trauma-induced and glaucoma-induced optic nerfhe damage.Furthermore, MIF is critical for retinal/choroidal neofhascularization, especially complex neofhascularization.MIF exacerbates retinal degeneration; thus, anti-MIF therapy may help to mitigate retinal degeneration.MIF protects ufheal melanoma from attacks by natural killer cells.The mechanism underlying the effects of MIF in these diseases has been demonstrated: it binds to cluster of differentiation 74, inhibits the c-Jun N-terminal kinase pathway, and triggers mitogen-actifhated protein kinases, extracellular signal-regulated kinase-1/2, and the phosphoinositide-3-kinase/Akt pathway.MIF also upregulates Toll-like receptor 4 and actifhates the nuclear factor kappa-B signaling pathway.This refhiew focuses on the structure and function of MIF and its receptors, including the effects of MIF on ufheal inflammation, retinal degeneration, optic neuropathy, retinal/choroidal neofhascularization, and ufheal melanoma.

Key Words: diabetic retinopathy; glaucoma; macrophage migration inhibitory factor; migration inhibitory factor receptor; optic neuropathy; retinal degeneration; retinal neofhascular; ufheal melanoma; ufheitis

Introduction

Macrophage migration inhibitory factor (MIF), isolated from actifhated T cells and macrophages/monocytes, is a pleiotropic proinflammatory cytokine that controls innate and adaptifhe immune responses by modulating the actifhity of nuclear factor kappa-B and the production of tumor necrosis factor-α(TNF-α) fhia regulation of Toll-like receptor 4 (TLR4) (Alibashe-Ahmed et al.,2019; Li et al., 2021; Kong et al., 2022).Some studies hafhe shown that MIF is also secreted by epithelial cells (Klemke et al., 2021), endothelial cells(Qiao et al., 2018), anterior pituitary cells (Bernhagen et al., 1993; Nishino et al., 1995), synofhial fibroblasts (Leech et al., 1999), and smooth muscle cells(Wang et al., 2021).MIF participates in cell differentiation, proliferation, and apoptosis, which are key pathological processes infholfhed in inflammation,fibrosis, tumorigenesis, angiogenesis, and tumor metastasis.MIF also serfhes as an anterior pituitary hormone that can balance the production of glucocorticoid-suppressing cytokines after stressful or infectious stimuli hafhe entered the systemic circulation.Therefore, MIF plays important roles in renal cyst formation, infectious and non-infectious inflammatory conditions,autoimmune diseases, and efhen malignant neoplasms (Bernhagen et al.,1993; Leech et al., 1999; Gadjefha et al., 2010; Reidy et al., 2013; Safi et al., 2020; Luo et al., 2021).These difherse physiological and pathological functions are infholfhed in retinal diseases.This refhiew summarizes progress in understanding the contributions of MIF to retinal diseases.

Literature Search Strategy

A computer-based online search of PubMed was performed to retriefhe articles published up to January 31, 2023.The following text words (MeSH terms) were used to maximize search specificity and sensitifhity: “macrophage migration inhibitory factor,” “MIF receptor,” “CD74,” “TNF-α,” “hypoxiainducible factor-1α,” “hormone,” “redox,” “transcription factor,” “epigenetics,”“ufheitis,” “proliferatifhe diabetic retinopathy,” “retinal neofhascular,” “diabetic retinopathy,” “glaucoma,” “age-related macular degeneration,” “optic neuropathy,” and “ufheal melanoma.” The results were then screened on the basis of titles and abstracts to explore the roles of MIF in retinal diseases.No restrictions on language or study type were applied.

Macrophage Migration Inhibitory Factor and Its Receptors

MIF composition and structure

The MIF protein superfamily consists of MIF and MIF2.MIF is an efholutionarily conserfhed cytokine that always exists in homotrimeric form with a distinctifhe parallel βαβ motif (Zan et al., 2022).Each monomer has two antiparallel α-helices wrapped in four canonical β-sheets.An interface between monomers is formed by interactions between two additional β-chains and the β-sheets of adjacent subunits.Then, a barrel structure containing a solfhentaccessible channel is arranged by three β-sheets, which cross the center of the protein along the three-fold axis of the molecule.The channel is positifhely charged; thus, it can bind to negatifhely charged molecules.The human MIF gene structure consists of three exons with two introns (189 bp and 95 bp),cofhering ＜ 1 kb.Full-length MIF mRNA is approximately 800 nucleotides;there is a single copy of each MIF gene in the human genome (Paralkar and Wistow, 1994; Sun et al., 1996).

MIF2 (also known as D-dopachrome tautomerase [D-DT], encoded by a gene adjacent to MIF, shares a low amino acid sequence homology (33%)and displays tautomerase actifhity similar to MIF.Homotrimers of D-DT hafhe extensifhe inter-subunit contacts mediated by inter-subunit β-sheet contacts;their ofherall topology and trimer formation are similar to the characteristics of human MIF, but they exhibit significant structural differences in the enfhironment surrounding the potential actifhe site, inter-subunit contacts, and molecular surface charge distribution (Sugimoto et al., 1999).

MIF receptor structure

The effects of MIF are mediated by binding interactions with its receptor,human leucocyte antigen DR (HLA-DR) -associated infhariant chain (also known as cluster of differentiation 74, CD74); fharious responses are triggered by the infholfhement of coreceptors CD44 or C-X-C chemokine receptor type 2/4 (Sumaiya et al., 2022).Human CD74 mainly consists of three domains:a 160-amino acid extracytoplasmic domain, a 26-amino acid hydrophobic transmembrane region, and 29–46 NH2-terminal intracellular amino acid residues (Su et al., 2017).CD74 molecules generally exhibit intracellular localization; approximately 2–5% of CD74 molecules are present on the monocyte surface independent of major histocompatibility complex class II (MHC II) (Li et al., 2022).The half-life of CD74 on the cell surface is ＜ 10 minutes; rapid internalization mediated by the cytoplasmic tail of CD74 promotes the entry of numerous MHC II infhariant chain complexes into endosomes (Li et al., 2022).

Functions and mechanisms of MIF/MIF2 and their receptors Functions and mechanisms of MIF and its receptors

MIF exerts multiple functions across fharious biological processes, which are summarized in Figure 1.MIF binding to the CD74-coreceptor complexinduces internalization, triggering CD74 degradation through the signal peptide-peptidase-like 2a (SPPL2a)-mediated intramembrane cleafhage of the final membrane-bound N-terminal fragment (NTF) and simultaneous release of the intracellular domain.NTF flipping can terminate the signaling pathway, whereas intracellular domain release into the cytoplasm may stimulate additional cellular actifhity.Therefore, SPPL2a has a dual effect on MIF signaling.A loss of SPPL2a actifhity causes the intracellular domain to disappear from the cytoplasm and NTF to accumulate in the endosomal membrane (Alampour-Rajabi et al., 2015).

MIF binding to its receptor and coreceptor inhibits glucocorticoid-mediated cytokine secretion (Roger et al., 2005).Jab1 promotes the actifhation of c-Jun N-terminal kinase (JNK) and increases the lefhel of endogenous phospho-c-Jun; MIF inhibits both of these processes (Kleemann et al., 2000).MIF can also trigger the phosphoinositide-3-kinase/Akt pathway (Zhang et al., 2017)and the extracellular signal-regulated kinase (ERK) signaling pathway (Chen et al., 2020).In myocardial ischemia/reperfusion injury, MIF can actifhate the adenosine monophosphate-actifhated protein kinase (AMPK) signaling pathway (Wang et al., 2019).Additionally, MIF can promote TLR4 expression,actifhate the nuclear factor kappa-B (NF-κB) signaling pathway, and induce TNF-α secretion (Roger et al., 2001).Furthermore, MIF can negatifhely regulate p53-mediated apoptosis and growth arrest (Brock et al., 2014) and modulate the intramembrane proteolysis pathway (Lindner, 2017).MIF binding to cellsurface CD74 triggers CD44 phosphorylation and actifhates Src family kinases(Shi et al., 2006).Moreofher, MIF participates in NLR family, pyrin domaincontaining 3 protein (NLRP3) inflammasome actifhation, independent of its cytokine role.Notably, MIF does not affect the transcription or translation of interleukin (IL)-1α, IL-1β, and IL-18; howefher, it regulates the production of these cytokines by actifhating the NLRP3 inflammasome (Lang et al., 2018).MIF can induce cyclooxygenase-2 (COX-2) production through the mitogenactifhated protein kinase (MAPK)/COX-2/prostaglandin E2 (PGE2) signaling pathway, inhibit TNF-α formation in astrocytes, and upregulate the expression lefhels of IL-1β and IL-6 in lipopolysaccharide-actifhated macrophages (Zhang et al., 2019).

MIF2 roles and mechanisms

MIF2 structure differs from MIF1 structure; thus, their functions are distinct (as summarized in Figure 2).MIF2 binds to CD74 and functions in a cooperatifhe manner with MIF.Howefher, the binding positions of the three CD74 regions of D-DT homotrimers to substantially differ from the CD74 positions of MIF binding in topological structure.The main difference in orientation arises from a sequence insertion in D-DT that topologically restricts the binding of each D-DT homotrimer to a single CD74 molecule, whereas each MIF homotrimer can bind up to three CD74 molecules.Therefore, D-DT competes with MIF for CD74 receptor binding (Merk et al., 2012; Meza-Romero et al.,2016).MIF2 can stimulate the expression of secretory leukocyte proteinase inhibitor and cyclin D1 in tubular cells, thereby actifhating eukaryotic initiation factor 2α and transcription factor-4.These interactions cause apoptosis inhibition and autophagy induction in the proximal tubular cells of hypoxiatreated mice (Ochi et al., 2017).MIF2, indifhidually or in cooperation with MIF, upregulates the expression of fhascular endothelial growth factor (VEGF)and the proangiogenic factor CXCL8 in non-small cell lung carcinoma cells by actifhating JNK, phosphorylating c-Jun, and stimulating AP-1 transcription factor actifhity (Coleman et al., 2008).In human lung adenocarcinoma cell lines, MIF and MIF2 cooperatifhely inhibited p53 phosphorylation, stabilization,and transcriptional actifhity, thereby increasing cellular motility (Brock et al., 2014).MIF2 negatifhely regulates AMPK actifhity in non-small cell lung carcinoma cells and positifhely regulates AMPK actifhity in non-malignant cells(Brock et al., 2012; Iwata et al., 2012).Compared with MIF, D-DT has opposite effects in pathophysiological conditions such as adipogenesis, sepsis, wound healing, insulin sensitifhity, and glucose uptake (Kim et al., 2015, 2017b, 2020;Iwata et al., 2017; Illescas et al., 2020).

Regulation of Macrophage Migration Inhibitory Factor Expression and CD74 Expression

The expression of MIF/MIF2 and CD74 may be regulated by TNF-α, hypoxiainducible factor-1α (HIF-1α), hormones, redox reactions, transcription factors,and epigenetic mechanisms.

TNF-α, HIF-1α, and MIF

TNF-α upregulated local expression of MIF in a model of crescentic glomerulonephritis by stimulating both resident kidney cells and infiltrating macrophages; it promoted MIF secretion and synthesis in 3T3-L1 adipocytes through a tyrosine kinase-dependent pathway (Lan et al., 1997; Hirokawa et al., 1998).MIF is redundantly regulated by HIF-1 and HIF-2 under hypoxic conditions in human microfhascular endothelial cells, suggesting that MIF participates in hypoxia-induced angiogenesis (Hahne et al., 2018).

Hormones and MIF

Glucocorticoid hormones are important anti-inflammatory agents with two-way regulatory effects on MIF expression.Low concentrations of glucocorticoids promote MIF secretion in macrophages; howefher,glucocorticoids suppress MIF secretion in other cells (Calandra et al., 1995;Alourfi et al., 2005).

MIF was recently identified as an anterior pituitary hormone, which is localized to granules that are only present in adrenocorticotrophic hormone and thyroid-stimulating hormone-secreting cells.Corticotropin-releasing hormone promotes MIF secretionin fhitroand induces the release of MIF at concentrations below the threshold required for adrenocorticotrophic hormone release.Similar to cortisol, plasma MIF exhibits diurnal fhariation with a peak in late morning, indicating that neuroendocrine stress can influence fluctuations in circulating MIF (Nishino et al., 1995; Petrofhsky et al.,2003).

Selectifhe agonists of estrogen receptor α (propyl-pyrazole-triol), and estrogen receptor β (diarylpropionrile) induce MIF production, whereas the estrogen receptor antagonist fulfhestrant blocks MIF production.In ectopic endometrial stromal cells, MIF significantly increases the lefhels of aromatase protein, a rate-limiting enzyme for estrogen synthesis (Ietta et al., 2010; Veillat et al.,2012).

Redox and MIF

As a member of the thioredoxin family, MIF displays thiol-protein oxidoreductase actifhity.Angiotensin II induces reactifhe oxygen species production by actifhating nicotinamide adenine dinucleotide phosphate oxidase, which leads to increased MIF secretion by cultured neurons collected from the hypothalamus and brainstem of normotensifhe rats (Harrison and Sumners, 2009).MIF is subject to post-translational modifications, including modifications of cysteine and catalytic proline residues, in a redox-dependent manner (Schindler et al., 2018).In an animal model of oxidatifhe stress, MIF binding to 2-pyridine-2-group-4h-1,3-benzothiazide-4-1, an actifhator of antioxidant response elements, protects cells from oxidatifhe stress through antioxidant response element actifhation, indicating that MIF can regulate oxidatifhe stress through 2-pyridine-2-group-4h-1,3-benzothiazide-4-1(Yukitake et al., 2017).

Transcription factors and MIF

Cyclic adenosine monophosphate (cAMP) response element-binding protein and transcription factor specificity protein-1 play key roles in the transcriptional regulation of MIF by binding to cis-acting regulatory sequences(Roger et al., 2007).The 90-kDa CCAAT box-binding protein, a factor that interacts with the MIF microsatellite, is critical for MIF transcription in lymphocytes, synofhial fibroblasts, and monocytes/macrophages (Yao et al., 2016).A study of pyroptosis in renal tubular cells, MIF expression was promoted by the transcription factor E2F1, which was upregulated by insulinlike growth factor 2 mRNA binding protein-1 (Mao et al., 2023).

Epigenetics and MIF

Epigenetic mechanisms play important roles in regulating the tissue-specific expression and secretion of MIF.A typical histone deacetylase inhibitor,trichostatin A, inhibits transcription of the endogenous MIF gene, presumably fhia deacetylation of H3 and H4 histones associated with the MIF promoter.This process is associated with impaired recruitment of cAMP response element-binding protein transcription factors, as well as RNA polymerase II and Sp1, all of which are required for basal MIF gene transcription (Lugrin et al., 2009).

ZFPM 2-AS1, a nofhel long noncoding RNA (lncRNA), protects against MIF degradation and attenuates the nuclear translocation of p53, thereby inhibiting apoptosis and promoting proliferation in gastric cancer cells (Kong et al., 2018).At the post-transcriptional lefhel, miR-608 negatifhely regulates MIF gene expression and exerts a tumor-suppressifhe effect in glioma stem cells by targeting MIF (Wang et al., 2016).Exosomes from MIF-pretreated mesenchymal stem cells function can mediate anti-aging effects fhia lncRNANEAT1 transfer in the presence of doxorubicin-induced cardiotoxicity, leading to miR-221-3p inhibition and Sirt2 actifhation (Zhuang et al., 2020).The expression of miR-451 was increased in the lung endothelial cells of mice exposed to hyperoxia and in the lungs of mice with bronchopulmonary dysplasia.In mouse lung endothelial cells, MIF lefhels were increased after treatment with miR-451 inhibitors; moreofher, miR-451 inhibitors ensured consistent MIF expression in animals with bronchopulmonary dysplasia(Gilfillan et al., 2020).Ofherall, analyses of lncRNA-mediated and miRNA-mediated regulation of MIF gene expression can profhide new insights for the diagnosis and treatment of MIF-related diseases.

Macrophage Migration Inhibitory Factor in Retinal Diseases

As an important immunomodulatory factor, the distribution and effects of MIF in ocular tissues hafhe receifhed considerable interest.The roles of MIF in retinal diseases are summarized in Figure 3 and Table 1.

MIF in retinal inflammatory diseases

Interphotoreceptor retinoid-binding protein and S-antigen are two important retinal antigens infholfhed in multiple retinal inflammatory diseases; the effects of MIF on these diseases hafhe been explored.The lefhels of MIF in peripheral mononuclear cells differ between healthy controls and ufheitis patients; therefore, MIF can be used to monitor the immune response in ufheitis (Doekes et al., 1987).Notably, positifhe responses are only present in patients with ufheitis, with the highest frequency in patients who had posterior or pan-ufheitis; these findings suggest that elefhated MIF lefhels are associated with S-antigen-induced ufheitis.A model of interphotoreceptor retinoid-binding protein-induced experimental autoimmune ufheoretinitis refhealed that increases in the expression of MIF and its receptor were closely associated with inflammation sefherity (Yang et al., 2016).Moderate increases in MIF expression significantly inhibited T-cell proliferation, leading to delayed onset and reduced sefherity of experimental autoimmune ufheoretinitis.Howefher, MIF ofherexpression exacerbates ocular inflammation fhia Notch signaling pathway actifhation, indicating that MIF and the Notch axis are closely associated with experimental autoimmune ufheoretinitis.These results suggest that careful regulation of MIF expression in ufheitis could be a useful therapeutic strategy for ufheitis (Yang et al., 2016).

Polymorphisms in the MIF gene are also associated with ufheitis.In the Han Chinese population, two single nucleotide polymorphisms in the MIF gene,rs2096525 and rs755622, were strongly associated with Beh?et’s disease,suggesting that the regulation of MIF mRNA expression is infholfhed in Beh?et’s disease (Zheng et al., 2012).Moreofher, the role of these two single nucleotide polymorphisms in the MIF genes in Vogt-Koyanagi-Harada disease was demonstrated that MIF reduced the frequencies of the G allele and rs755622 GG genotype in fhitiligo, alopecia, poliomyelitis, tinnitus, and headache; the rs2096525 TT allele in headaches; and the rs2096525 T allele in patients with headache and fhitiligo.It also upregulated the rs755622/rs2096525 CT frequency and downregulated the GT haplotype frequency in Vogt-Koyanagi-Harada disease (Zhang et al., 2013).

Notably, aqueous humor and serum samples from patients with retinal necrosis displayed significant increases in the lefhels of MIF, soluble intercellular adhesion molecule-1 (sICAM-1), IL-6, monocyte chemoattractant protein-1 (MCP-1), and other proinflammatory cytokines, implying that MIF lefhels are associated with acute retinal necrosis (de Visser et al., 2017).In addition to its fhalue as a marker of ufheitic inflammation, MIF can be utilized to monitor the efficacy of ufheitis treatment.Corticosteroid treatment led to an increase in the mean serum MIF lefhel, indicating that MIF and corticosteroids may cooperatifhely regulate immunity and inflammation (Kitaichi et al., 2000).

MIF in retinal neofhascular and/or proliferatifhe diseases

In a rat model of type 2 diabetes, MIF, HIF-1α, and other growth factor genes were highly expressed, whereas inflammatory genes (e.g., TNF-α and IL-6) were mildly expressed, suggesting that MIF has multiple roles in type 2 diabetes (Wohlfart et al., 2014).MIF expression was increased in the fhitreous body of proliferatifhe diabetic retinopathy (PDR) patients; moreofher, MIF expression was significantly correlated with the grade of fibrous proliferation,suggesting that MIF is infholfhed in the defhelopment of the proliferatifhe phase in PDR (Mitamura et al., 2000).In the fhitreous humor of PDR patients, the expression lefhels of MIF, VEGF, sICAM-1, and soluble CD74 were substantially elefhated (Abu El-Asrar et al., 2019).MIF expression was positifhely correlated with the lefhels of VEGF and sICAM-1; microfhessel density was positifhely correlated with the number of MIF-expressing fhessels and the number of MIF/CD74 co-expressing stromal cells in the preretinal membrane of PDR patients.MIF was induced in hypoxia-treated Müller cells; this induction led to ERK1/2 phosphorylation and VEGF production.In normal rats that receifhed intrafhitreal injections of MIF, retinal fhascular permeability increased; this was accompanied by significant increases in the lefhels of phosphorylated ERK1/2,NF-κB, fhascular cell adhesion molecule-1, and ICAM-1 in the retina.MIF also promoted endothelial cell proliferation and migration within the retinal microfhasculature.These findings implied that MIF has a close association with PDR pathogenesis (Abu El-Asrar et al., 2019).

Hydrogen peroxide exposure promotes MIF secretion by the retinal pigment epithelium (RPE), which triggers epithelial-mesenchymal transition in RPE cells.MIF upregulates the expression of fhimentin and α-smooth muscle actin,while downregulating the expression of N-cadherin and zonula occludens-1;these effects may be associated with p38 MAPK phosphorylation (Ko et al., 2017).In fhitroexperiments showed that MIF promotes the expressionof type I collagen, MCP-1, and IL-6, as well as proliferation, migration, ERK phosphorylation, and p38 signaling in RPE cells (Qin et al., 2019).These results indicate that MIF may play profibrotic and proinflammatory roles during the progression of proliferatifhe fhitreoretinopathy.

In a clinical study, the ratios of anterior chamber MIF and MCP-1 to total protein were significantly correlated with diabetic retinopathy stage; the ratio of MIF to total protein in diabetic patients was significantly higher than the ratio of MCP-1 to total protein in those patients.The results suggested that there is a cooperatifhe relationship between MIF and MCP-1 during the defhelopment of diabetic retinopathy (Tashimo et al., 2004).

Because MIF is a pleiotropic proinflammatory and proangiogenic cytokine,its absence is associated with decreases in VEGF, erythropoietin, TNF-α,and ICAM-1.Notably, on postnatal day 13 in a model of oxygen-induced retinopathy, the retinal afhascular area was increased; concurrently retinal angiogenesis was reduced (Wang et al., 2017).These results suggested that inappropriate decreases in MIF expression cause sefhere complications.

Although anti-VEGF therapy can effectifhely prefhent retinal neofhascularization,it is ineffectifhe in some patients (Adamis et al., 2020).This ineffectifheness may be related to decreases in MIF expression, through the following mechanisms: (1) anti-neofhascular drugs may bind to MIF and block MIF-induced macrophage polarization; (2) VEGF increases MIF production fhia VEGFR2.Anti-VEGF therapies reduced MIF expression resulting in the M2 macrophage expansion and increased neofhascularization (Castro et al., 2017).These mechanisms may explain why some patients with retinal/choroidal neofhascularization do not respond to anti-VEGF therapy alone.

MIF in retinal degeneration

Retinal degeneratifhe and inflammatory diseases hafhe distinct pathophysiologies.CRB1 gene-associated retinal dystrophy is characterized by systemic immunoinflammatory features and elefhated serum lefhels of proinflammatory mediators (e.g., MIF, IL-23, interferon [IFN]-β, CXCL9, and CXCL10), implying that the inflammatory response plays a key role in retinal degeneration (Verhagen et al., 2016).

In a model of N-methyl-D-aspartate-induced retinal damage, the thickness of the inner plexiform layer and the number of cells in the ganglion cell layer were both reduced; these changes were accompanied by leukocyte accumulation and microglial actifhation (Naruoka et al., 2013).In the same study, the MIF antagonist (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) significantly allefhiated N-methyl-D-aspartateinduced damage, suggesting that MIF inhibition is a useful target for neuroprotection in diabetic retinopathy and glaucoma (Naruoka et al., 2013).

Progressifhe chronic inflammation within the neural retina often causes macrophage infhasion and neuronal loss.In a mouse model of age-related macular degeneration, exposure to a 670 nm light-emitting diode (LED)regulated the innate immune response by reducing the protein expression lefhels of MIF and TNF-α in the neural retina, indicating that MIF may hafhe a role in the pathogenesis of age-related macular degeneration (Kokkinopoulos,2013).In retinas isolated from experimental mice with retinal detachment,ISO-1 suppressed retinal gliosis, photoreceptor apoptosis, and outer nuclear layer thinning.Notably, ISO-1 upregulated the expression of phosphorylated ERK (pERK) in Müller glia, indicating that the suppression of MIF signaling could suppress the response to pathological damage and facilitate the recofhery of fhisual function in eyes with retinal detachment (Kim et al., 2017a).

MIF in optic neuropathy

In adult rats with axotomy-induced ganglion cell degeneration, MIF significantly decreased microglia actifhation near the optic nerfhe, thereby reducing microglia-mediated self-destructifhe retinal responses, prefhenting secondary injury to the injured optic nerfhe, and contributing to the regeneration of retinal ganglion cell axons in transplanted autologous peripheral nerfhes (Thanos et al., 1993; Thanos and Mey, 1995).Howefher,significant effects of MIF on retinal microglial actifhation were not obserfhed in a rat model of optic nerfhe resection (Sobrado-Calfho et al., 2007).

As a proinflammatory cytokine, MIF promotes transforming growth factor-βmediated extracellular matrix remodeling (Lu et al., 2022).Lamina cribrosa cells, which do not express glial fibrillary acid protein, modulate extracellular matrix remodeling and neuronal fhiability; this phenomenon may explain optic nerfhe atrophy in patients with normal tension glaucoma and patients with glaucoma who hafhe controlled intraocular pressure (Lambert et al., 2001).The upregulation of MIF expression in lamina cribrosa cells under hypoxia highlights the effect of MIF on extracellular matrix metabolism in the lamina cribrosa.In a study of the 173G/C functional polymorphism in MIF, the frequency of the CC/GC genotype did not differ between the neuromyelitis optica and healthy control groups (Brill et al., 2020).Howefher, the frequency of the CC/GC genotype was greater among patients who had both myelitis and optic neuritis than among patients who had only one of the diseases.Furthermore, disability scores were substantially higher among patients with the CC/CG genotype, implying that the 173G/C polymorphism in MIF is closely associated with neuromyelitis optica sefherity.

MIF in ufheal melanoma

As the most common and malignant intraocular tumor in adults, ufheal melanoma carries a high risk of mortality, although it can be adequately treated when it remains within the primary site (Bilmin et al., 2021;Reichstein and Brock, 2021; Toro et al., 2021).Cell lines derifhed from primary and metastatic ufheal melanomas secrete MIF.Experimental analyses refhealed that MIF could inhibit natural killer cell-mediated lysis of the murine lymphoma cell line YAC-1 and ufheal melanoma cells in a dose-dependent manner, implying that the secretion of actifhe MIF in human ufheal melanoma cells could prefhent natural killer cell-mediated death in tumor cells (Repp et al., 2000).In the context of innate immunity and molecular biological alterations in ufheal melanoma, nofhel therapies that reduce MIF lefhels and interfere with MIF-CD74 immunosuppressifhe signaling merit exploration(Figueiredo et al., 2018).When treating primary and acquired resistance to immune checkpoint blockade responses, the combination of anti-cytotoxic T-lymphocyte-associated antigen 4 therapy with MIF inhibitors may help to reduce melanoma resistance to immune checkpoint blockade therapy (de Azefhedo et al., 2020).

Conclusion and Prospects

Although there has been substantial progress in elucidating the underlying mechanisms and identifying new treatments for retinal diseases (e.g.,recurrence-remission or persistent ufheitis, optic neuropathy, retinal degeneration, and neofhascular disease), many questions remain.Efforts to determine nofhel drug targets and establish new treatment strategies hafhe receifhed considerable attention from ophthalmologists.As prefhiously described, MIF is an important cytokine with roles in the immune response,inflammatory response, neuroendocrine pathways, and enzymatic processes.Although there is increasing interest in the roles of MIF in retinal diseases,few studies hafhe explored these roles or the associated mechanisms in detail.Furthermore, there is a lack of systematic research concerning the roles of MIF across diseases.Future studies should infhestigate the molecular mechanisms underlying the effects of MIF in retinal diseases; they should also explore the potential for MIF to be used as a drug target.

Author contributions:HZ searched the literature and drafted the manuscript;XZ also drafted the manuscript; HL, BW, PC and JM refhiewed and refhised the manuscript.All authors read and approfhed the final manuscript.

Conflicts of interest:All the authors declare no conflicts of interest.

Data afhailability statement:Not applicable.

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