BET protein inhibition in macrophages enhances dorsal root ganglion neurite outgrowth in female mice
Palomés Borrajo, Georgina (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Navarro, X. (Xavier) (Universitat Autònoma de Barcelona. Institut de Neurociències)
Penas Pérez, Clara (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)

Date:	2022
Abstract:	Peripheral nerve regeneration is limited after injury, especially in humans, due to the large distance the axons have to grow in the limbs. This process is highly dependent on the expression of neuroinflammatory factors produced by macrophages and glial cells. Given the importance of the epigenetic BET proteins on inflammation, we aimed to ascertain if BET inhibition may have an effect on axonal outgrowth. For this purpose, we treated female mice with JQ1 or vehicle after sciatic nerve crush injury and analyzed target reinnervation. We also used dorsal root ganglion (DRG) culture explants to analyze the effects of direct BET inhibition or treatment with conditioned medium from BET-inhibited macrophages. We observed that although JQ1 produced an enhancement of IL-4, IL-13, and GAP43 expression, it did not have an effect on sensory or motor reinnervation after crush injury in vivo. In contrast, JQ1 reduced neurite growth when interacting directly with DRG neurons ex vivo, whereas conditioned medium from JQ1-treated macrophages promoted neurite outgrowth. Therefore, BET-inhibited macrophages secrete pro-regenerative factors that induce neurite outgrowth, and that may counteract the direct inhibition of BET proteins in neurons in vivo. Finally, we observed an activation of the STAT6 pathway in DRG explants treated with conditioned medium from JQ1-treated macrophages. In conclusion, this study demonstrates that BET protein inhibition in macrophages provides a mechanism to enhance axonal outgrowth. However, specific targeting of BET proteins to macrophages will be needed to efficiently enhance functional recovery after nerve injury.
Grants:	Agencia Estatal de Investigación PID2019-108496 Ministerio de Economía y Competitividad RD16/0011/0014 Ministerio de Sanidad y Consumo CB06/05/1105
Note:	Altres ajuts: acords transformatius de la UAB
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	BET proteins ; Cytokines ; Inflammation ; Neurite outgrowth ; Regeneration
Published in:	Journal of Neuroscience Research, Vol. 100 Núm. 6 (june 2022) , p. 1331-1346, ISSN 1097-4547

DOI: 10.1002/jnr.25036
PMID: 35218246

16 p, 1.5 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Neurociències (INc)
Articles > Research articles
Articles > Published articles