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Table 2 M2 inducing agents used in disease models

From: Neuroinflammation and M2 microglia: the good, the bad, and the inflamed

Disease or injury Treatment Outcome Reference
Traumatic brain injury Rosiglitazone 24 hours after controlled cortical impact, rosiglitazone was given intraperitoneally. Seven days later there were decreased cortical lesions and reduced glial activation. A reduction in apoptotic cells was also seen. [72]
Ischemia Rosiglitazone Rosiglitazone was given orally before ischemia was induced. Treatment reduced damage in the hippocampal CA1 region and delayed neural death. Elevated levels of IL-4 and IL-13 were seen after treatment. [90]
Spinal cord injury Rosiglitazone Rosiglitazone was injected intraperitoneally every 12 hours after spinal cord injury for 12 days. Treatment decreased tissue damage and significantly reduced apoptosis in damaged tissue. TNFα and IL1β reduction was also observed. [91]
Mesenchymal stem cell transplantation Transplantation in an injured spinal cord resulted in elevated levels of IL-4 and IL-13 and reduced TNFα and IL-6. There was functional locomotion improvement as well as reduced scarring and more preserved axons. [85]
Granulocyte colony-stimulating factor Granulocyte colony-stimulating factor was injected for three consecutive days after spinal cord injury. Enhanced Arg1 and CD206 mRNA and reduced iNOS, TNFα, and IL-1β were seen. There was also reduced NF-κB activity. No locomotor tests were performed, but the authors concluded that this is a viable method to reduce acute phase inflammation after spinal cord injury. [89]
Substance P Substance P was injected intravenously immediately, 24, and 48 hours after spinal cord injury. Injected rats had reduced iNOS, IL-6, and TNFα mRNA levels and elevated amounts of Arg1 and IL-10. M2 cells were observed at the lesion site. Spinal cord lesions were significantly smaller and injected mice had improved locomotion scores. [92]
Multiple sclerosis or EAE IL-4 Herpes simplex virus carrying an IL-4 sequence was injected into the CNS of mice with EAE. Treatment delayed progression of disease and improved clinical score. Significant reduction in inflammation and axon degeneration was also seen. [93]
IL-4 Used transduced T cells carrying a retroviral gene to express IL-4 during EAE. Mice showed delayed onset and reduced severity of disease. [94]
IL-4 Adenoviral-vector-carrying IL-4 was injected into cerebrospinal fluid of mice induced to have EAE. Reduced clinical score and improvement in several neurophysiological parameters were seen in injected mice. [95]
IL-10 Used adult neural stem cells engineered to express IL-10. Intraperitoneal injection during EAE reduced CNS inflammation and lessened demyelination. Additionally there was enhanced remyelination. [96]
Glatiramer acetate Glatiramer acetate is a synthetic peptide shown to be beneficial in treating relapsing and remitting multiple sclerosis. It shifts the CNS environment from Th1 to Th2 and induces secretion of anti-inflammatory cytokines. [97]
IL-33 Intraperitoneal injection of IL-33, 12–20 days after induction of EAE, reduced inflammatory cytokines and improved clinical scores. Elevated M2 cells were also seen around lesions. [98]
Alzheimer’s disease Glatiramer acetate Vaccination with glatiramer acetate caused a reduction in amyloid β plaques in APP/PS1 mice. The effect is thought to be mediated in part by glatiramer acetate inducing IL-4, which can counteract the effect of amyloid β on microglia. Glatiramer acetate vaccination also reversed cognitive decline. [99]
IL-4 Intracerebral injection of IL-4 and IL-13 reduced amyloid β plaque load in APP23 mice with Alzheimer’s disease. The decrease was accompanied with improved cognition and upregulation of Arg1 and YM1 positive M2 cells. [32]
IL-4 AAV carrying an IL-4 sequence was injected intrahippocampally in 3-month-old APP/PS1 mice. Five months later there was a reduction in amyloid β plaques, improvement in the Morris water maze memory task, and elevated neurogenesis. [100]
IL-10 AAV expressing IL-10 was injected intrahippocampally in 3-month-old APP/PS1 mice. Unlike previous experiments with IL-4, AAV-IL10 did not clear amyloid β plaque at 5 months. However, neurogenesis was improved. [101]
DSP-8658 DSP-8658 (a PPAR γ/α agonist) treatment was able to increase microglial uptake of amyloid β in APP/PS1 mice. The mechanism of action was thought to be via CD36 upregulation on microglia. [102]
Bexarotene Bexarotene (retinoid X receptor agonist) in APP/PS1 and APP/PS1-21 mice with Alzheimer’s disease led to reduced amyloid load 14 days after oral treatment. The plaque reduction was associated with improved order habituation behavior. [103]
  1. AAV, adeno-associated virus; APP, amyloid precursor protein; CNS, central nervous system; EAE, experimental autoimmune encephalitis.