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.