Human microglia-derived proinflammatory cytokines facilitate human retinal ganglion cell development and regeneration
Murali Subramani1, Brandon Lambrecht1, Iqbal Ahmad1
1Department of Ophthalmology and Visual Science, University of Nebraska Medical Center, Omaha, NE, USA.
Abstract:
Microglia (μG), the resident immune cells in the central nervous system, surveil the parenchyma to maintain the structural and functional homeostasis of neurons. Besides, they influence neurogenesis and synaptogenesis through complement-mediated phagocytosis. Emerging evidence suggests that μG may also influence development through proinflammatory cytokines. Here, we examined the premise that tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β), the two most prominent components of the μG secretome, influence retinal development, specifically the morphological and functional differentiation of human retinal ganglion cells (hRGCs). Using controlled generation of hRGCs and human μG (hμG) from pluripotent stem cells, we demonstrate that TNF-α and IL-1β secreted by unchallenged hμG did not influence hRGC generation. However, their presence significantly facilitated neuritogenesis along with the basal function of hRGCs, which involved the recruitment of the AKT/mTOR pathway. We present ex vivo evidence that proinflammatory cytokines may play an important role in the morphological and physiological maturation of hRGCs, which may be recapitulated for regeneration.
Insights
Proinflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β), secreted by microglia, significantly enhanced the neurite growth and function of human retinal ganglion cells (hRGCs). This study highlights their role in retinal development and potential for regeneration.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Microglia (microG) are central nervous system immune cells crucial for neuronal homeostasis.
- Microglia influence neurogenesis and synaptogenesis via phagocytosis.
- Emerging evidence suggests microglia's role in development through proinflammatory cytokines.
Purpose of the Study:
- To investigate the influence of TNF-α and IL-1β from microglia on human retinal ganglion cell (hRGC) development.
- To determine the impact of these cytokines on hRGC morphological and functional differentiation.
Main Methods:
- Controlled generation of hRGCs and human microglia (hmicroG) from pluripotent stem cells.
- Assessment of TNF-α and IL-1β effects on hRGC generation and differentiation.
- Analysis of the AKT/mTOR pathway involvement.
Main Results:
- TNF-α and IL-1β from unchallenged hmicroG did not affect hRGC generation.
- These cytokines significantly facilitated hRGC neuritogenesis and basal function.
- The AKT/mTOR pathway was recruited in response to the cytokines.
Conclusions:
- Proinflammatory cytokines TNF-α and IL-1β play a significant role in the morphological and physiological maturation of hRGCs.
- These findings suggest potential therapeutic applications for retinal regeneration.
