Macrophage migration inhibitory factor: A multifaceted cytokine implicated in multiple neurological diseases

Leyton-Jaimes, Marcel F.; Kahn, Joy; Israelson, Adrian

doi:10.1016/j.expneurol.2017.06.021

Cited by 62 publications

(56 citation statements)

References 138 publications

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“…Multiple cell types in CNS express this protein, such as microglia, fibroblasts, pituitary cells, endothelial cells, neurons, and neural stem cell progenitors [35]. Aberrant expression of MIF has shown to result in several pathological diseases of the CNS including Alzheimer’s disease, autism spectrum disorders, encephalomyelitis, and tumorigenesis [35–38]. In the acute phase of spinal cord injury, MIF contributes to neuropathological impairments through promoting neuronal death and inflammatory activation [14, 16].…”

Section: Discussionmentioning

confidence: 99%

Macrophage migration inhibitory factor facilitates production of CCL5 in astrocytes following rat spinal cord injury

Zhou

Guo

Zhu

et al. 2018

J Neuroinflammation

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BackgroundAstrocytes act as immune effector cells with the ability to produce a wide array of chemokines and cytokines in response to various stimuli. Macrophage migration inhibitory factor (MIF) is inducibly expressed in injured spinal cord contributing to excessive inflammation that affects motor functional recovery. Unknown is whether MIF can facilitate inflammatory responses through stimulating release of chemokines from astrocytes following spinal cord injury.MethodsFollowing the establishment of the contusion spinal cord injury rat model, the correlation of chemokine (C-C motif) ligand 5 (CCL5) expression with that of MIF was assayed by Western blot, ELISA, and immunohistochemistry. Immunoprecipitation was used to detect MIF interaction with membrane CD74 receptor. Intracellular signal transduction of MIF/CD74 axis was analyzed by transcriptome sequencing of primary astrocytes and further validated by treatment of various inhibitors. The effects of CCL5 released by astrocytes on macrophage migration were performed by transwell migration assay. The post-injury locomotor functions were assessed using the Basso, Beattie, and Bresnahan (BBB) locomotor scale.ResultsThe protein levels of chemokine CCL5/RANTES were remarkably increased in the astrocytes of rat injured spinal cord, in parallel with the expression of MIF. Treatment of MIF inhibitor 4-IPP in the lesion sites resulted in a significant decrease of CCL5 protein levels. In vitro study revealed MIF was capable of facilitating CCL5 production of astrocytes through interaction with CD74 membrane receptor, and knockdown of this receptor attenuated such effects. Production of CCL5 in astrocytes was significantly blocked by inhibitor of c-Jun N-terminal kinase, rather than by those of ERK and P38. Recombinant CCL5 protein was found to be more effective in promoting migration of M2- compared to M1-type macrophages.ConclusionCollectively, these data reveal a novel function of MIF in regulation of CCL5 release from astrocytes, which in turn favors for recruitment of inflammatory cells to the injured site of the spinal cord, in association with activation of excessive inflammation.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1297-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Macrophage migration inhibitory factor facilitates production of CCL5 in astrocytes following rat spinal cord injury

Zhou

Guo

Zhu

et al. 2018

J Neuroinflammation

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“…migration inhibitory factor (MIF). MIF is a homotrimer, which has been implicated in both extracellular and intracellular functions and is synthesized as a cytoplasmic protein (11,42). MIF acts as a cytokine (43) and was also shown to have chaperone-like activity (44) and thiol oxidoreductase activity (45), in addition to a tautomerase activity (46).…”

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confidence: 99%

AAV2/9-mediated overexpression of MIF inhibits SOD1 misfolding, delays disease onset, and extends survival in mouse models of ALS

Leyton-Jaimes

Kahn

Israelson

2019

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

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Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by the loss of upper and lower motor neurons. Transgenic mice that overexpress mutant SOD1 develop paralysis and accumulate misfolded SOD1 onto the cytoplasmic faces of intracellular organelles, including mitochondria and endoplasmic reticulum (ER). Recently, macrophage migration inhibitory factor (MIF) was shown to directly inhibit mutant SOD1 misfolding and binding to intracellular membranes. In addition, complete elimination of endogenous MIF accelerated disease onset and late disease progression, as well as shortened the lifespan of mutant SOD1 mice with higher amounts of misfolded SOD1 detected within the spinal cord. Based on these findings, we used adeno-associated viral (AAV) vectors to overexpress MIF in the spinal cord of mutant SOD1G93A and loxSOD1G37R mice. Our data show that MIF mRNA and protein levels were increased in the spinal cords of AAV2/9-MIF–injected mice. Furthermore, mutant SOD1G93A and loxSOD1G37R mice injected with AAV2/9-MIF demonstrated a significant delay in disease onset and prolonged survival compared with their AAV2/9-GFP–injected or noninjected littermates. Moreover, these mice accumulated reduced amounts of misfolded SOD1 in their spinal cords, with no observed effect on glial overactivation as a result of MIF up-regulation. Our findings indicate that MIF plays a significant role in SOD1 folding and misfolding mechanisms and strengthen the hypothesis that MIF acts as a chaperone for misfolded SOD1 in vivo and may have further implications regarding the therapeutic potential role of up-regulation of MIF in modulating the specific accumulation of misfolded SOD1.

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“…Furthermore, there are no significant variations in the levels of MIF in the CNS in the course of life, thus supporting the concept that MIF could play a homeostatic role due to its involvement in the isomerization of catecholamine derivatives to neuromelanin precursors [16]. Moreover, MIF seems to be involved in various inflammatory, vascular, traumatic, neoplastic, and neurodegenerative diseases of the nervous system, such as multiple sclerosis (MS), stroke and cerebral ischemia, autism-spectrum disorders, spinal cord injury, depression, glioblastoma, and Alzheimer disease (AD) [16][17][18][19][20]. Overall, the role of MIF in the CNS is not yet fully understood and further studies are warranted to clarify its precise mode of action in these conditions.…”

Section: The Role Of Mif In the Central Nervous System (Cns)mentioning

confidence: 64%

The Dichotomic Role of Macrophage Migration Inhibitory Factor in Neurodegeneration

Basile

Battaglia

Bruno

et al. 2020

IJMS

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Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine expressed by different cell types and exerting multiple biological functions. It has been shown that MIF may be involved in several disorders, including neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), and Huntington disease (HD), that represent an unmet medical need. Therefore, further studies are needed to identify novel pathogenetic mechanisms that may translate into tailored therapeutic approaches so to improve patients’ survival and quality of life. Here, we reviewed the preclinical and clinical studies investigating the role of MIF in ALS, PD, and HD. The emerging results suggest that MIF might play a dichotomic role in these disorders, exerting a protective action in ALS, a pathogenetic action in HD, and a yet undefined and debated role in PD. The better understanding of the role of MIF in these diseases could allow its use as a novel diagnostic and therapeutic tool for the monitoring and treatment of the patients and for eventual biomarker-driven therapeutic approaches.

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Macrophage migration inhibitory factor: A multifaceted cytokine implicated in multiple neurological diseases

Cited by 62 publications

References 138 publications

Macrophage migration inhibitory factor facilitates production of CCL5 in astrocytes following rat spinal cord injury

Macrophage migration inhibitory factor facilitates production of CCL5 in astrocytes following rat spinal cord injury

AAV2/9-mediated overexpression of MIF inhibits SOD1 misfolding, delays disease onset, and extends survival in mouse models of ALS

The Dichotomic Role of Macrophage Migration Inhibitory Factor in Neurodegeneration

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