A fatty acid amide activates myeloid cells and improves neurovascular outcomes in retinal degeneration
Neurovasculoglial cross-talk underlying breakdown of the neurovascular unit is a central, yet poorly understood, component of many neurodegenerative disorders of the CNS, including retinal disease. Primary fatty acid amides have been identified to regulate this cross-talk between vasculature and neuronal tissues, but specific molecules and mechanisms remain unresolved. Here we show, using an unbiased high-resolution metabolomics screen, that erucamide, a 22:1 monounsaturated omega-9 fatty acid amide, is highly dysregulated during photoreceptor degeneration in mice. In vivo delivery of erucamide using organosilane-modified porous silicon nanoparticles activated retinal myeloid cells, leading to the upregulation of angiogenic and neurotrophic cytokines that limited vascular and neuronal degeneration. We identified TMEM19 as a binding protein for erucamide that is crucial for myeloid cell activation and subsequent neuroprotection. These findings reveal a previously unknown primary fatty acid amide pathway that modulates neuroimmune interactions during retinal degenerative diseases. We propose erucamide and analogs as candidate therapeutics.
Authors
- Roberto Bonelli (ORCID: https://orcid.org/0000-0003-2676-1230)
- Martin Friedlander (ORCID: https://orcid.org/0000-0003-4238-9651)
- Ruhan Fan (ORCID: https://orcid.org/0000-0003-0626-849X)
- Dale L. Boger (ORCID: https://orcid.org/0000-0002-3966-3317)
- Shreyosree Chatterjee
- Benjamin F. Cravatt (ORCID: https://orcid.org/0000-0001-5330-3492)
- Michael J. Sailor (ORCID: https://orcid.org/0000-0002-4809-9826)
- Sarah Giles (ORCID: https://orcid.org/0000-0003-0177-2654)
- Gary Siuzdak (ORCID: https://orcid.org/0000-0002-4749-0014)
- Edith Aguilar (ORCID: https://orcid.org/0000-0003-2507-6637)
- Ayumi Usui‐Ouchi (ORCID: https://orcid.org/0000-0003-2974-0830)
- Daisuke Ogasawara (ORCID: https://orcid.org/0000-0002-2178-4698)
- Sanahan Vijayakumar (ORCID: https://orcid.org/0000-0003-2493-1902)
- Guoqin Wei (ORCID: https://orcid.org/0000-0001-6050-4911)
- Yi-Xiang Wang (ORCID: https://orcid.org/0000-0002-4021-4228)
- KEVIN EADE
- Qinglin Yang
- Katie Biscocho
- Jacob Robinson
- Helena Pham
- Peter Westenskow
Institutions
- Scripps Research Institute (US)
- Scripps Health (US)
- Scripps Institution of Oceanography (US)
- University of California San Diego (US)
- The Lowy Medical Research Institute (US)
- Scripps Clinic Medical Group (US)
- Scripps (United States) (US)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2026-06-19
- DOI
- https://doi.org/10.1038/s41593-026-02341-w
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- California Institute for Regenerative Medicine
- Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada
- National Institutes of Health
- National Eye Institute