Discovery of novel MIF inhibitors that attenuate microglial inflammatory activation by structures-based virtual screening and in vitro bioassays

Xu, Lei; Zhang, Yao; Pan, Jie; Wang, Puqing; Tian, Sheng; Li, Huanting; Gao, Bowen; Hou, Tingjun; Zhen, Xuechu; Zheng, Longtai

doi:10.1038/s41401-021-00753-x

Cited by 16 publications

(12 citation statements)

References 63 publications

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“…Macrophage migration inhibitory factor (MIF) is a multipotent cytokine involved in promoting proinflammatory response. [ 57 ] It is known to be the key factor for the activation of microglia in chronic neuroinflammation and possibly accelerates neurodegeneration. [ 56 , 58 ] It has also been implicated in controlling the cytokine release related to tau hyperphosphorylation and neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Botulinum Neurotoxin Induces Neurotoxic Microglia Mediated by Exogenous Inflammatory Responses

Ambrin,

Kang,

Van Do

et al. 2024

Advanced Science

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Botulinum neurotoxin serotype A (BoNT/A) is widely used in therapeutics and cosmetics. The effects of multi‐dosed BoNT/A treatment are well documented on the peripheral nervous system (PNS), but much less is known on the central nervous system (CNS). Here, the mechanism of multi‐dosed BoNT/A leading to CNS neurodegeneration is explored by using the 3D human neuron‐glia model. BoNT/A treatment reduces acetylcholine, triggers astrocytic transforming growth factor beta, and upregulates C1q, C3, and C5 expression, inducing microglial proinflammation. The disintegration of the neuronal microtubules is escorted by microglial nitric oxide, interleukin 1β, tumor necrosis factor α, and interleukin 8. The microglial proinflammation eventually causes synaptic impairment, phosphorylated tau (pTau) aggregation, and the loss of the BoNT/A‐treated neurons. Taking a more holistic approach, the model will allow to assess therapeutics for the CNS neurodegeneration under the prolonged use of BoNT/A.

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Section: Discussionmentioning

confidence: 99%

Botulinum Neurotoxin Induces Neurotoxic Microglia Mediated by Exogenous Inflammatory Responses

Ambrin,

Kang,

Van Do

et al. 2024

Advanced Science

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“…[59,60] Furthermore, it has been observed that MIF inhibitor can reduce the production of TNF-𝛼 and IL-1𝛽 in microglia by downregulating the transcriptional activity of the nuclear factor-kappa B (NF-𝜅B) pathway in various immune cells. [61][62][63] Studies have shown that the suppression of the NF-𝜅B pathway can promote the recovery of SCI. [64,65] Based on the understanding of pathways, we demonstrated that the function of MPSS in excessive inflammation inhibition was mainly attributed to the reduction in cell activation, such as microglia, T cells, and macrophages.…”

Section: Discussionmentioning

confidence: 99%

Single‐Cell Sequencing Reveals the Optimal Time Window for Anti‐Inflammatory Treatment in Spinal Cord Injury

Wen

et al. 2023

Advanced Biology

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Though the occurrence of neuroinflammation after spinal cord injury (SCI) is essential for antigen clearance and tissue repair, excessive inflammation results in cell death and axon dieback. The effect of anti‐inflammatory medicine used in clinical treatment remains debatable owing to the inappropriate therapeutic schedule that does not align with the biological process of immune reaction. A better understanding of the immunity process is critical to promote effective anti‐inflammatory therapeutics. However, cellular heterogeneity, which results in complex cellular functions, is a major challenge. This study performs single‐cell RNA sequencing by profiling the tissue proximity to the injury site at different time points after SCI. Depending on the analysis of single‐cell data and histochemistry observation, an appropriate time window for anti‐inflammatory medicine treatment is proposed. This work also verifies the mechanism of typical anti‐inflammatory medicine methylprednisolone sodium succinate (MPSS), which is found attributable to the activation inhibition of cells with pro‐inflammatory phenotype through the downregulation of pathways such as TNF, IL2, and MIF. These pathways can also be provided as targets for anti‐inflammatory treatment. Collectively, this work provides a therapeutic schedule of 1–3 dpi (days post injury) to argue against classical early pulse therapy and provides some pathways for target therapy in the future.

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“…Total mRNA was isolated from macrophages or brain tissues using TRIzol reagent (Invitrogen, USA) according to a previously reported protocol 28 . cDNA was synthesized from mRNA with a random primer using an M-MLV reverse transcriptase kit (Takara, Japan) in a reaction of 1 µg of total RNA.…”

Section: Methodsmentioning

confidence: 99%

Sigma-1 receptor-regulated efferocytosis by infiltrating circulating macrophages/microglial cells protects against neuronal impairments and promotes functional recovery in cerebral ischemic stroke

Zhang¹,

Li²,

Tao³

et al. 2023

Theranostics

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Background: Efferocytosis of apoptotic neurons by macrophages is essential for the resolution of inflammation and for neuronal protection from secondary damage. It is known that alteration of the Sigma-1 receptor (Sig-1R) is involved in the pathological development of some neurological diseases, including ischemic stroke. The present study aimed to investigate whether and how Sig-1R regulates the phagocytic activity of macrophages/microglia and its significance in neuroprotection and neurological function in stroke. Methods: The roles of Sig-1R in the efferocytosis activity of microglia/macrophages using bone marrow-derived macrophages (BMDMs) or using Sig-1R knockout mice subjected to transient middle artery occlusion (tMCAO)-induced stroke were investigated. The molecular mechanism of Sig-1R in the regulation of efferocytosis was also explored. Adoptive transfer of Sig-1R intact macrophages to recipient Sig-1R knockout mice with tMCAO was developed to observe its effect on apoptotic neuron clearance and stroke outcomes. Results: Depletion of Sig-1R greatly impaired the phagocytic activity of macrophages/microglia, accordingly with worsened brain damage and neurological defects in Sig-1R knockout mice subjected to tMCAO. Adoptive transfer of Sig-1R intact bone marrow-derived macrophages (BMDMs) to Sig-1R knockout mice restored the clearance activity of dead/dying neurons, reduced infarct area and neuroinflammation, and improved long-term functional recovery after cerebral ischemia. Mechanistically, Sig-1R-mediated efferocytosis was dependent on Rac1 activation in macrophages, and a few key sites of Rac1 in its binding pocket responsible for the interaction with Sig-1R were identified. Conclusion: Our data provide the first evidence of the pivotal role of Sig-1R in macrophage/microgliamediated efferocytosis and elucidate a novel mechanism for the neuroprotection of Sig-1R in ischemic stroke.

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Discovery of novel MIF inhibitors that attenuate microglial inflammatory activation by structures-based virtual screening and in vitro bioassays

Cited by 16 publications

References 63 publications

Botulinum Neurotoxin Induces Neurotoxic Microglia Mediated by Exogenous Inflammatory Responses

Botulinum Neurotoxin Induces Neurotoxic Microglia Mediated by Exogenous Inflammatory Responses

Single‐Cell Sequencing Reveals the Optimal Time Window for Anti‐Inflammatory Treatment in Spinal Cord Injury

Sigma-1 receptor-regulated efferocytosis by infiltrating circulating macrophages/microglial cells protects against neuronal impairments and promotes functional recovery in cerebral ischemic stroke

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