FKBP5 activates mitophagy by ablating PPAR-γ to shape a benign remyelination environment.

Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease of the central nervous system (CNS) that is characterized by myelin damage, followed by axonal and ultimately neuronal loss, which has been found to be associated with mitophagy. The etiology and pathology of MS remain elusive. However, the role of FK506 binding protein 5 (FKBP5, also called FKBP51), a newly identified gene associated with MS, in the progression of the disease has not been well defined. Here, we observed that the progress of myelin loss and regeneration in Fkbp5ko mice treated with demyelination for the same amount of time was significantly slower than that in wild-type mice, and that mitophagy plays an important regulatory role in this process. To investigate the mechanism, we discovered that the levels of FKBP5 protein were greatly enhanced in the CNS of cuprizone (CPZ) mice and the myelin-denuded environment stimulates significant activation of the PINK1/Parkin-mediated mitophagy, in which the important regulator, PPAR-γ, is critically regulated by FKBP5. This study reveals the role of FKBP5 in regulating a dynamic pathway of natural restorative regulation of mitophagy through PPAR-γ in pathological demyelinating settings, which may provide potential targets for the treatment of demyelinating diseases.

The Dectin-1 Receptor Signaling Pathway Mediates the Remyelination Effect of Lentinan through Suppression of Neuroinflammation and Conversion of Microglia.

Demyelinating diseases such as multiple sclerosis (MS) are chronic inflammatory autoimmune diseases and involve demyelination and axonal degeneration. Microglia rapidly respond to changes in the environment by altering morphotype and function during the progressive disease stage. Although substantial progress has been made in the drug development for MS, treatment of the progressive forms of the disease remains unsatisfactory. There is great interest in identifying novel agents for treating MS. Lentinus edodes is a traditional food, which can improve physiological function. Lentinan (LNT), a type of polysaccharide extracted from mushroom Lentinus edodes, is an anti-inflammatory and immunomodulatory agent. Here, we studied the remyelination effects of LNT and its therapeutic target in regulating the functions of neuroinflammation. We found that LNT enhanced remyelination and rescued motor deficiency by regulating dectin-1 receptor to inhibit neuroinflammation and microglial cell transformation. LNT promoted the conversion of microglial cells from the M1 status induced by LPS to the M2 status, enhanced the anti-inflammatory markers IL-10 and BDNF, inhibited inflammatory markers TNF-α and IL-1ß, and downregulated the microglia activation and oligodendrocyte and astrocyte proliferation by modulating dectin-1. If we injected the dectin-1-specific inhibitor laminarin (Lam), the remyelination effects induced by LNT were completely abolished. Thus, these results suggest that LNT is a novel and potential therapeutic agent that can rescue MS neuroimmune imbalance and remyelination through a dectin-1 receptor-dependent mechanism.