TABLE 4.

Summary of the important beneficial or detrimental mediators secreted by microglia and astrocytes

Mediators
Beneficial	Cells	Outcome	References	Observations/validation	References
Tumor necrosis factor‐α (Tnf‐α)	Microglia	Tnf‐α up‐regulates following CPZ‐feeding in the corpus callosum and co‐localized with microglia. Tnf‐α−/− mice show delayed oligodendrocyte degeneration and demyelination.	(Arnett et al., 2001)	Contradictory outcomes. In vitro: Microglial secretion of Tnf‐α causes reduction of neuronal cells survival. In vivo (experimental autoimmune neuritis model): Microglia‐mediated secretion of Tnf‐α causes demyelination.	(Hemmer et al., 2001; Stoll et al., 1993)
Insulin‐like growth factor‐1 (Igf‐1)	Microglia	Up‐regulation of Igf‐1 reduces CPZ‐induced demyelination.	(Mason et al., 2000)	In vivo (CamKIIα‐cre; Igf1rflox/− Tg mice): Igf‐1 mutation leads to the disruption of oligodendrocyte accumulation and proliferation at the site of demyelination resulting in inadequate remyelination.	(Mason et al., 2003)
Sphingosine‐1 phosphate (S1P)	Microglia	Microglial secretion of S1P enhances OPC recruitment in lysolecithin‐injected mice.	(Lombardi et al., 2019)	In vivo (CPZ model): Reduction of demyelination, axonal injury and glial activation with increased number of oligodendrocytes occurs following S1P treatment.	(Kim et al., 2011)
Activin‐A	Microglia	Microglial polarization shifts from M1 to M2 phenotype. Blocking of M2‐derived Activin secretion prevents oligodendrocyte differentiation in lysolecithin and ethidium bromide‐injected rats.	(Miron et al., 2013)	In vivo (PdgfraCre; Acvr1bf/f Tg mice): Activin receptor signaling is essential for oligodendrocyte differentiation and myelin formation. Ex vivo (organoleptic cerebellar brain explants): Activin‐A increases remyelination in lysolecithin‐mediated demyelinated section.	(Dillenburg et al., 2018)
Interferon‐β (Ifn‐β)	Microglia	Microglial secretion of Ifn‐β during the peak stage of EAE removes myelin debris following autoimmune‐mediated demyelination in the spinal cord.	(Kocur et al., 2015)	In vivo (Theiler's murine encephalomyelitis virus model): Contradictory outcome. Short‐term (5 weeks) Ifn‐α/β treatment reduces demyelination but long‐term (16 weeks) treatment exacerbates demyelination.	(Njenga et al., 2000)
Tissue inhibitor of metalloproteinases‐1 (Timp‐1)	Astrocytes	Astrocytic production of Timp‐1 causes OPC proliferation.	(Houben et al., 2020)	In vitro: Cultured CNS progenitor cells from Timp‐1 KO mice lack Ng2+ OPCs. Timp‐1 administration increase the number of OPCs. In vivo (Timp‐1 KO mice): Reduction of myelinated axons and myelin compactness is seen in mice lacking Timp‐1.	(Moore et al., 2011)
Detrimental
Colony‐stimulating factor‐1 (Csf‐1)	Microglia	Injection of Csf‐1 into the CNS induces microglial activation and demyelination. Csf‐1 inhibitor (PLX3397)‐mediated microglial depletion reduces the oligodendrocyte loss, astrocyte activation and demyelination.	(Marzan et al., 2021)	In vivo (lysolecithin model): Reduction of microglia is observed in the mice lacking Csf‐1 (Csf‐1−/− mice). Moreover, Csf‐1 deficiency reduces the microglial recruitment at the site of demyelination. Axonal injury and impairment of remyelination are also associated with the deletion of Csf‐1.	(Wylot et al., 2019)
Interleukin‐3 (Il‐3)	Microglia	Il‐3 is a pro‐inflammatory cytokine. Microglial secretion of Il‐3 evokes demyelination in Gfap‐Il‐3 transgenic mice.	(Chiang et al., 1996)	In vivo (EAE model): Injection of Il‐3 exacerbates EAE symptoms and cerebral inflammation. Anti‐Il‐3 monoclonal antibody administration reduces EAE symptoms.	(Renner et al., 2016)
Heat shock protein‐60 (Hsp‐60)	Microglia	Production of Hsp‐60 by activated microglia (in the LPS model) causes OPC apoptosis.	(Li et al., 2017)	In vitro: OPCs (Oli‐neu) culture with microglia and Hsp‐60 leads to the reduction of oligodendrocyte viability. In vivo (C57Bl/6J): Intrathecal injection of Hsp‐60 causes oligodendrocyte loss and myelin basic protein reduction.	(Rosenberger et al., 2015)
Nuclear factor kappa‐B (Nfk‐B)	Astrocytes	Astrocytic secretion of Nfk‐B causes oligodendrocyte degeneration.	(Brück et al., 2012)	In vivo: (p65 [RelA]) ‐ an Nfk‐B transcription factor in EAE model: Deletion of RelB reduces disease severity.	(Gupta et al., 2019)