Retinoic acid increases phagocytosis of myelin by macrophages

Traumatic injuries of the central nervous system (CNS) are followed by the accumulation of cellular debris including proteins and lipids from myelinated fiber tracts. Insufficient phagocytic clearance of myelin debris influences the pathological process because it induces inflammation and blocks axonal regeneration. We investigated whether ligands of nuclear receptor families retinoic acid receptors (RARs), retinoid X receptors, peroxisome proliferator-activated receptors, lipid X receptors, and farnesoid X receptors increase myelin phagocytosis by murine bone marrow-derived macrophages and Raw264.7 cells. Using in vitro assays with 3,3 '-dioctadecyloxacarbocyanine perchlorate- and pHrodo-labeled myelin we found that the transcriptional activator all-trans retinoic acid (RA)enhanced endocytosis of myelin involving the induction of tissue transglutaminase-2. The RAR-dependent increase of phagocytosis was not associated with changes in gene expression of receptors Fc gamma R1, Fc gamma R2b, Fc gamma R3, TREM2, DAP12, CR3, or MerTK. The combination of RA and myelin exposure significantly reduced the expression of M1 marker genes inducible nitric oxide synthase and interleukin-1 beta and increased expression of transmembrane proteins CD36 and ABC-A1, which are involved in lipid transport and metabolism. The present results suggest an additional mechanism for therapeutic applications of RA after CNS trauma. It remains to be studied whether endogenous RA-signaling regulates phagocytosis in vivo.