Subretinal mononuclear phagocytes induce cone segment loss via IL-1β
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, France
- Keck School of Medicine of the University of Southern California, United States
Abstract
Photo-transduction in cone segments (CS) is crucial for high acuity daytime vision. For ill-defined reasons, CS degenerate in retinitis pigmentosa (RP) and in the transitional zone (TZ) of atrophic zones (AZ), which characterize geographic atrophy (GA). Our experiments confirm the loss of cone segments (CS) in the TZ of GA patients and show their association with subretinal CD14+mononuclear phagocyte (MP) infiltration that is also reported in RP. Using human and mouse MPs in vitro and inflammation-prone Cx3cr1GFP/GFP mice in vivo, we demonstrate that MP derived IL-1β leads to severe CS degeneration. Our results strongly suggest that subretinal MP accumulation participates in the observed pathological photoreceptor changes in these diseases. Inhibiting subretinal MP accumulation or Il-1β might protect the CS and help preserve high acuity daytime vision in conditions characterized by subretinal inflammation, such as AMD and RP.
Article and author information
Author details
Xavier Guillonneau
Funding
Agence Nationale de la Recherche (MACLEAR)
- Sébastien Augustin
- Elisa Dominguez
- Sophie Lavalette
- Shulong Justin Hu
- Lourdes Siquieros
- José-Alain Sahel
- Michel Paques
- Xavier Guillonneau
- Florian Sennlaub
Labex (lifescience)
- Chiara M Eandi
- Hugo Charles Messance
- Sébastien Augustin
- Elisa Dominguez
- Sophie Lavalette
- Shulong Justin Hu
- Lourdes Siquieros
- José-Alain Sahel
- Ramin Tadayoni
- Michel Paques
- Xavier Guillonneau
- Florian Sennlaub
adps-allianz
- Chiara M Eandi
- Hugo Charles Messance
- Sébastien Augustin
- Elisa Dominguez
- Sophie Lavalette
- Shulong Justin Hu
- Lourdes Siquieros
- José-Alain Sahel
- Ramin Tadayoni
- Michel Paques
- Xavier Guillonneau
- Florian Sennlaub
National Institutes of Health (EY015851)
- Cheryl Mae Craft
National Institutes of Health (EY03040)
- Cheryl Mae Craft
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experimental protocols and procedures were approved by the local animal care ethics committee (00156.02; C 92-032-02 )
Human subjects: Volunteers provided written and informed consent for the human monocyte expression studies, which were approved by the Centre national d'ophthalmologie des Quinze-Vingt hospital (Paris, France) ethics committees (no. 913572)
Copyright
© 2016, Eandi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,579
- views
-
- 331
- downloads
-
- 73
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Further reading
-
- Neuroscience
By influencing calcium homeostasis, local protein synthesis and the endoplasmic reticulum, a small protein called Rab10 emerges as a crucial cytoplasmic regulator of neuropeptide secretion.
-
- Neuroscience
Millions of Americans suffering from Opioid Use Disorders face a high risk of fatal overdose due to opioid-induced respiratory depression (OIRD). Fentanyl, a powerful synthetic opioid, is a major contributor to the rising rates of overdose deaths. Reversing fentanyl overdoses has proved challenging due to its high potency and the rapid onset of OIRD. We assessed the contributions of central and peripheral mu opioid receptors (MORs) in mediating fentanyl-induced physiological responses. The peripherally restricted MOR antagonist naloxone methiodide (NLXM) both prevented and reversed OIRD to a degree comparable to that of naloxone (NLX), indicating substantial involvement of peripheral MORs to OIRD. Interestingly, NLXM-mediated OIRD reversal did not produce aversive behaviors observed after NLX. We show that neurons in the nucleus of the solitary tract (nTS), the first central synapse of peripheral afferents, exhibit a biphasic activity profile following fentanyl exposure. NLXM pretreatment attenuates this activity, suggesting that these responses are mediated by peripheral MORs. Together, these findings establish a critical role for peripheral MORs, including ascending inputs to the nTS, as sites of dysfunction during OIRD. Furthermore, selective peripheral MOR antagonism could be a promising therapeutic strategy for managing OIRD by sparing CNS-driven acute opioid-associated withdrawal and aversion observed after NLX.
