Persistent Activation of the Innate Immune Response in AdultDrosophilaFollowing Radiation Exposure During Larval Development

Abstract

Cranial radiation therapy (CRT) is an effective treatment for pediatric central nervous system malignancies, but survivors often suffer from neurological and neurocognitive side effects that occur many years after radiation exposure. Although the biological mechanisms underlying these deleterious side effects are incompletely understood, radiation exposure triggers an acute inflammatory response that may evolve into chronic inflammation, offering one avenue of investigation. Recently, we developed a Drosophila model of the neurotoxic side effects of radiation exposure. Here we use this model to investigate the role of the innate immune system in response to radiation exposure. We show that the innate immune response and NF-ĸB target gene expression is activated in the adult Drosophila brain following radiation exposure during larval development, and that this response is sustained in adult flies weeks after radiation exposure. We also present preliminary data suggesting that innate immunity is radioprotective during Drosophila development. Together our data suggest that activation of the innate immune response may be beneficial initially for survival following radiation exposure but result in long-term deleterious consequences, with chronic inflammation leading to impaired neuronal function and viability at later stages. This work lays the foundation for future studies of how the innate immune response is triggered by radiation exposure and its role in mediating the biological responses to radiation. These studies may facilitate the development of strategies to reduce the deleterious side effects of CRT.

Drosophila Exhibit Divergent Sex-Based Responses in Transcription and Motor Function After Traumatic Brain Injury

“…In our analysis, we have also observed significant changes in transcript levels in several immune pathway genes in response to brain injury (Figure 3). The Drosophila innate immune system is highly conserved with mammals and consists primarily of the Toll, Immunodeficiency (Imd) and Janus Kinase protein and the Signal Transducer and Activator of Transcription (JAK-STAT) pathways, which together combat fungal and bacterial infections (58,59). Previous studies have explored activation of JAK-STAT (60) in response to injury but we did not see any change in gene expression associated with this pathway.…”

The utilization of small non‐mammals in traumatic brain injury research: A systematic review

“…118 The innate immune system is highly conserved between flies and humans. 119,120 The antimicrobial peptides (AMP) gene was upreg- which all regulated by the Toll, Imd, and JAK-STAT pathways 121 and depleted after 7 days of the injury. The short duration of genes upregulation is the same as findings in the mammalian model, where inflammatory gene spikes after TBI but dies down during subsequent days.…”

Mammalian Models of Traumatic Brain Injury and a Place for Drosophila in TBI Research

“…The Allada lab used glial targeted translating ribosome affinity purification in combination with RNA sequencing (TRAP-seq) and identified glial immune pathways as mediators of TBI effects in flies injured using dCHI (van Alphen et al, 2018). The Drosophila innate immune system consists of the Immunodeficiency (Imd), Toll and JAK-STAT pathways, which combat fungal and bacterial infections (Lemaitre and Hoffmann, 2007; Sudmeier et al, 2015). An upregulation of several immune genes like alrm (astrocytic leucine-rich repeat molecule, astrocyte-specific), moody (blood brain barrier), wunen-2 (wun2, astrocyte-specific), reversed polarity (repo, pan-glial) , and gli (gliotactin, expressed in peripheral glia) was seen 24 h after TBI in this study.…”