Attenuation of Macrophage Migration Inhibitory Factor-Stimulated Signaling <i>via</i> <i>S</i>-Nitrosylation

Abstract

Nitric oxide (NO) is a key signaling molecule that has various effects via S-nitrosylation, a reversible post-translational modification that affects the enzymatic activity, localization, and metabolism of target proteins. As chronic nitrosative stress correlates with neurodegeneration, the targets have received focused attention. Macrophage migration inhibitory factor (MIF) plays a pivotal role in the induction of gene expression to control inflammatory responses. MIF acts as a ligand for CD74 receptor and activates the Src-p38 mitogen-activated protein kinase (MAPK) cascade. MIF also elevates the expression of brain-derived neurotrophic factor (BDNF), which contributes to the viability of neurons. Here, we show that MIF is Snitrosylated by a physiological NO donor. Interestingly, the induction of S-nitrosylation resulted in a loss of MIF activity following stimulation of the Src and p38 MAPK signaling pathways and the induction of BDNF expression. Our results shed light on the pathogenic mechanisms of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.

The Role of Macrophage Migration Inhibitory Factor in Alzheimer′s Disease: Conventionally Pathogenetic or Unconventionally Protective?

“…In the former case, tailored inhibitors of MIF that are already in the clinical setting could be considered for pilot studies, which include the tautomerase inhibitor ibudilast that is marketed for different indications and is being repurposed for immunoinflammatory diseases [70], as well as anti-MIF mAb that have completed Phase I/II testing in cancer patients and the anti-CD74 mAb milatuzumab that is approved for patients with multiple myeloma [71]. It is also worth noting that the biological function of MIF can be inhibited by nitrosylation [72], and hence nitric oxide (NO) donors may indirectly promote MIF inhibition. Along these lines, we propose that together with NO-NSAID, that have been proven effective in both preclinical and clinical settings [73,74], and also other NO-donors such as the recently characterized lopinavir-NO and ritonavir-NO [75][76][77][78], deserve consideration as drugs to be used in the treatment of AD patients.…”

Emerging Role of the Macrophage Migration Inhibitory Factor Family of Cytokines in Neuroblastoma. Pathogenic Effectors and Novel Therapeutic Targets?

“…Moreover, it has been found that nitrosylation could dampen MIF activity [108]. Hence, another possible interesting approach may be to use nitric oxide (NO)-hybridized drugs, such as NO-aspirin or NO-hybridized antiretroviral protease inhibitors, including lopinavir-NO [87,92,94,95] and ritonavir-NO [87,93], for the treatment of NB and eventually other diseases in which MIF is involved.…”

The Dichotomic Role of Macrophage Migration Inhibitory Factor in Neurodegeneration

“…MIF mediates a neuroprotective effect via suppressing inflammatory responses, reducing the number of microglia and macrophages and displaying tyrosine hydroxylase-immunoreactive (TH-IR) neurons' enhanced fiber outgrowth [49]. MIF also inhibits apoptosis and neuronal loss, detoxifying catecholamine-derived [15] and also promoting BDNF expression [50], increasing MMP and decreasing cleaved-PARP [47].…”

“…Nakahara et al found that MIF was S-nitrosylated by a physiological NO donor in vitro and that MIF activity was reduced after S-nitrosylation [50]. Chronic nitrosative stress may be associated with neurodegeneration [50]. Moreover, MIF is involved in the control of inflammatory responses and also increases the expression of brain-derived neurotrophic factor (BDNF), which favors the viability of neurons [50].…”

“…Chronic nitrosative stress may be associated with neurodegeneration [50]. Moreover, MIF is involved in the control of inflammatory responses and also increases the expression of brain-derived neurotrophic factor (BDNF), which favors the viability of neurons [50]. Therefore, they suggested that MIF dysfunction caused by NO might be involved in the loss of neuronal viability associated with neurodegenerative diseases, such as PD [50].…”