Interleukin-13 immune gene therapy prevents CNS inflammation and demyelination via alternative activation of microglia and macrophages

Abstract

Detrimental inflammatory responses in the central nervous system are a hallmark of various brain injuries and diseases. With this study we provide evidence that lentiviral vector‐mediated expression of the immune‐modulating cytokine interleukin 13 (IL‐13) induces an alternative activation program in both microglia and macrophages conferring protection against severe oligodendrocyte loss and demyelination in the cuprizone mouse model for multiple sclerosis (MS). First, IL‐13 mediated modulation of cuprizone induced lesions was monitored using T2‐weighted magnetic resonance imaging and magnetization transfer imaging, and further correlated with quantitative histological analyses for inflammatory cell influx, oligodendrocyte death, and demyelination. Second, following IL‐13 immune gene therapy in cuprizone‐treated eGFP+ bone marrow chimeric mice, we provide evidence that IL‐13 directs the polarization of both brain‐resident microglia and infiltrating macrophages towards an alternatively activated phenotype, thereby promoting the conversion of a pro‐inflammatory environment toward an anti‐inflammatory environment, as further evidenced by gene expression analyses. Finally, we show that IL‐13 immune gene therapy is also able to limit lesion severity in a pre‐existing inflammatory environment. In conclusion, these results highlight the potential of IL‐13 to modulate microglia/macrophage responses and to improve disease outcome in a mouse model for MS. GLIA 2016;64:2181–2200

Hyperpolarized 13 C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

“…This supportive action of MPs is an essential step for subsequent remyelination at W6 and W6 + W6 recovery (49,55). Indeed, directing MPs toward an antiinflammatory phenotype before and during the first weeks of CPZ diet prevents in part oligodendrocyte cell death, demyelination, and astrogliosis (52,56). We chose to monitor CPZ mice at W4 and W6 of CPZ diet and after a subsequent period of 6 wk without CPZ because these three time points are characterized by different cellular events.…”

Down-regulation of interleukin 7 receptor (IL-7R) contributes to central nervous system demyelination

“…MS is a very heterogeneous disease of the central nervous system (CNS) and several mechanisms have been proposed to explain the underlying pathogenesis [1]. Experimental and clinical studies have indicated that the dysfunction of immune cells helps prevent autoimmune demyelination.…”

“…Demyelinating diseases are characterized by lesions that are associated with loss of myelin, while sparing axons in the nervous system [1]. Demyelination can affect the central nervous system (CNS), and is associated with the pathophysiology of various neurodegenerative diseases including demyelinating disorders like multiple sclerosis (MS) [1].…”

“…Demyelination can affect the central nervous system (CNS), and is associated with the pathophysiology of various neurodegenerative diseases including demyelinating disorders like multiple sclerosis (MS) [1]. Although the specific mechanisms of demyelination remain unclear, they include autoimmune and inflammatory responses involving T- and B-lymphocytes [2].…”

Molecular Targets for PET Imaging of Activated Microglia: The Current Situation and Future Expectations

“…However, no clinical effects of anti-inflammatory treatment were observed in clinical trials [42,43,44]. According to the recent knowledge on microglia polarization, promoting M2-microglia phenotype may be a promising target, as shown by studies on preclinical models of stroke [45], TBI [46], AD [47], PD [48], ALS [49], and multiple sclerosis (MS) [50]. Nonetheless, targeting neuroinflammation in these diseases is even more complex and a regimen of anti-inflammatory treatments is also crucial.…”