Interleukin 4 modulates microglia homeostasis and attenuates the early slowly progressive phase of amyotrophic lateral sclerosis

Abstract

Microglia activation is a commonly pathological hallmark of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), a devastating disorder characterized by a selective motor neurons degeneration. Whether such activation might represent a causal event rather than a secondary epiphenomenon remains elusive. Here, we show that CNS-delivery of IL-4—via a lentiviral-mediated gene therapy strategy—skews microglia to proliferate, inducing these cells to adopt the phenotype of slowly proliferating cells. Transcriptome analysis revealed that IL-4-treated microglia express a broad number of genes normally encoded by embryonic microglia. Since embryonic microglia sustain CNS development, we then hypothesized that turning adult microglia to acquire such phenotype via IL-4 might be an efficient in vivo strategy to sustain motor neuron survival in ALS. IL-4 gene therapy in SOD1G93A mice resulted in a general amelioration of clinical outcomes during the early slowly progressive phase of the disease. However, such approach did not revert neurodegenerative processes occurring in the late and fast progressing phase of the disease.

Metabolic Reprogramming during Microglia Activation

“…Briefly, cells were seeded in a 6-well plate at a density of 1 × 10 6 cells/well and polarized as described above. Cells were incubated with 0.5 µCi/mL [1,[2][3][4][5][6][7][8][9][10][11][12][13][14] C]-acetate (Perkin Elmer, Waltham, MA, USA for 24 h after which they were washed with phosphate-buffered saline and collected by scraping.…”

“…Moreover, the pro-inflammatory cytokine IL1β has been implicated in acute neuroinflammatory conditions and in several neurodegenerative diseases [9][10][11]. In contrast, in an anti-inflammatory state, microglia have protective and beneficial roles with IL4 mediating neuroprotection [8,[12][13][14]. According to current insights, microglia may play a decisive role in the outcome of neurological diseases including ischemia, neurodegeneration and traumatic events.…”

Maternal Type-I interferon signaling adversely affects the microglia and the behavior of the offspring accompanied by increased sensitivity to stress

“…Microglia are regulated by various factors within the central nervous system (CNS) microenvironment [37]. Among them are transforming growth factor beta, which is important for shaping the fate of microglia during development [38] and tightly controls their transcription profile in response to inflammatory signaling [39,40], methyl-CpG binding protein 2, which regulates microglial response to inflammatory stimuli [41], and interleukin-4, which stimulates microglial proliferation and modifies their inflammatory reaction following acute injury [42]. IFNβ is another important regulator of microglia, and was shown to modify and affect microglial inflammatory responses.…”

Short and long TNF‐alpha exposure recapitulates canonical astrogliosis events in human‐induced pluripotent stem cells‐derived astrocytes

“…IL‐6, IL‐2, and IL‐4 were described in this article as modulatory cytokines because they may induce and terminate inflammatory responses depending on the context of inflammation (Hoyer, Dooms, Barron, & Abbas, ; Luzina et al, ; Rothaug, Becker‐Pauly, & Rose‐John, ). These three cytokines are able to modulate microglial function (Akhmetzyanova, Kletenkov, Mukhamedshina, & Rizvanov, ; Recasens, Shrivastava, Almolda, Gonzalez, & Castellano, ; Rossi et al, ) as well as astrocyte activation (Alves et al, ; Brodie, Goldreich, Haiman, & Kazimirsky, ; Klein et al, ). Diapedesis and activation of other immunocompetent cells like neutrophils and lymphocytes within the brain can also be regulated by these modulatory cytokines (Erta, Quintana, & Hidalgo, ; Gadani, Cronk, Norris, & Kipnis, ; Gao et al, ).…”