Abstract
BackgroundAccumulating evidence suggests that disease-associated microglia (DAM), a recently discovered subset of microglia, plays a protective role in neurological diseases. Targeting DAM phenotypic transformation may provide new therapeutic options. However, the relationship between DAM and epilepsy remains unknown.MethodsAnalysis of public RNA-sequencing data revealed predisposing factors (such as dipeptidyl peptidase IV; DPP4) for epilepsy related to DAM conversion. Anti-epileptic effect was assessed by electroencephalogram recordings and immunohistochemistry in a kainic acid (KA)-induced mouse model of epilepsy. The phenotype, morphology and function of microglia were assessed by qPCR, western blotting and microscopic imaging.ResultsOur results demonstrated that DPP4 participated in DAM conversion and epilepsy. The treatment of sitagliptin (a DPP4 inhibitor) attenuated KA-induced epilepsy and promoted the expression of DAM markers (Itgax and Axl) in both mouse epilepsy model in vivo and microglial inflammatory model in vitro. With sitagliptin treatment, microglial cells did not display an inflammatory activation state (enlarged cell bodies). Furthermore, these microglia exhibited complicated intersections, longer processes and wider coverage of parenchyma. In addition, sitagliptin reduced the activation of NF-κB signaling pathway and inhibited the expression of iNOS, IL-1β, IL-6 and the proinflammatory DAM subset gene CD44.ConclusionThe present results highlight that the DPP4 inhibitor sitagliptin can attenuate epilepsy and promote DAM phenotypic transformation. These DAM exhibit unique morphological features, greater migration ability and better surveillance capability. The possible underlying mechanism is that sitagliptin can reduce the activation of NF-κB signaling pathway and suppress the inflammatory response mediated by microglia. Thus, we propose DPP4 may act as an attractive direction for DAM research and a potential therapeutic target for epilepsy.
Highlights
Accumulating evidence suggests that disease-associated microglia (DAM), a recently discovered subset of microglia, plays a protective role in neurological diseases
Inhibition of Dipeptidyl peptidase IV (DPP4) attenuates kainic acid (KA)-induced epilepsy To search for potential targets involved in DAM conversion, we collected both up- and downregulated gene profiles of epileptic hippocampus and gene-edited microglia from four independent Gene Expression Omnibus (GEO) datasets (Supplementary Figure 1A; Supplementary Table 2)
To observe the changes in epilepsy treated with DPP4 inhibitor sitagliptin, we evaluated epileptic seizures by EEG recordings (Fig. 1a)
Summary
Accumulating evidence suggests that disease-associated microglia (DAM), a recently discovered subset of microglia, plays a protective role in neurological diseases. Microglial phenotypic change plays a critical role in the pathogenesis of CNS diseases [4]. Recent studies have suggested that the polarization hypothesis is likely overly simplistic [7, 8]. Using single-cell RNA-sequencing (scRNA-seq) technology, Keren-Shaul et al identified a special microglial phenotype called disease-associated microglia (DAM) in neurodegenerative diseases [10,11,12]. Accumulating evidence suggests that DAM may act as a beneficial microglial phenotype in many CNS diseases [4]. The primary purpose of recent studies in the field of DAM research was to answer two major questions [4]: (1) Is DAM a widespread phenomenon in neurological diseases? The primary purpose of recent studies in the field of DAM research was to answer two major questions [4]: (1) Is DAM a widespread phenomenon in neurological diseases? (2) What is the underlying molecular mechanism?
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