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Drosophila caspase activity is required independently of apoptosis to produce active TNF/Eiger during nociceptive sensitization

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AbstractTumor necrosis factor (TNF) signaling is required for inflammatory nociceptive (pain) sensitization in Drosophila and vertebrates. Nociceptive sensitization in Drosophila larvae following UV-induced tissue damage is accompanied by epidermal apoptosis and requires epidermal-derived TNF/Eiger and the initiator caspase, Dronc. Major gaps remain regarding TNF function in sensitization, including the relationship between apoptosis/tissue damage and TNF production, the downstream signaling in this context, and the target genes that modulate nociceptive behaviors. Here, apoptotic cell death and thermal nociceptive sensitization are genetically and procedurally separable in a Drosophila model of UV-induced nociceptive sensitization. Activation of epidermal Dronc induces TNF-dependent but effector caspase-independent nociceptive sensitization in the absence of UV. In addition, knockdown of Dronc attenuated nociceptive sensitization induced by full-length TNF/Eiger but not by a constitutively soluble form. UV irradiation induced TNF production in both in vitro and in vivo, but TNF secretion into hemolymph was not sufficient to induce thermal nociceptive sensitization. Downstream mediators of TNF-induced sensitization included two TNF receptor-associated factors, a p38 kinase, and the transcription factor nuclear factor kappa B. Finally, sensory neuron-specific microarray analysis revealed downstream TNF target genes induced during thermal nociceptive sensitization. One of these, enhancer of zeste (E(z)), functions downstream of TNF during thermal nociceptive sensitization. Our findings suggest that an initiator caspase is involved in TNF processing/secretion during nociceptive sensitization, and that TNF activation leads to a specific downstream signaling cascade and gene transcription required for sensitization. These findings have implications for both the evolution of inflammatory caspase function following tissue damage signals and the action of TNF during sensitization in vertebrates.

Contributor(s)
Publisher
Springer Science and Business Media LLC
Date Issued
2017-05-11
Language
English
Type
Genre
Form
electronic document
Media type
Creator role
Faculty
Identifier
2041-4889
Has this item been published elsewhere?
Volume
8
Volume
5
Jo, . J., Im, . S. H., Babcock, . D. T., Iyer, . S. C., Gunawan, . F., Cox, . D. N., & Galko, . M. J. (2017). (Vols. 5). https://doi.org/10.1038/cddis.2016.474
Jo, Juyeon, Seol Hee Im, Daniel T Babcock, Srividya C Iyer, Felona Gunawan, Daniel N Cox, and Michael J Galko. 2017. https://doi.org/10.1038/cddis.2016.474.
Jo, Juyeon, et al. 11 May 2017, https://doi.org/10.1038/cddis.2016.474.