The effect of dipeptidyl peptidase IV on disease-associated microglia phenotypic transformation in epilepsy

Abstract

Background Accumulating 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. Methods Analysis 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. Results Our 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. Conclusion The 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.

Blockade of Kv1.3 Potassium Channel Inhibits Microglia-Mediated Neuroinflammation in Epilepsy

“…The inactive NF-κB signaling pathway induced by the kappa opioid receptor (KOR) participated in suppressing neuronal injury and regulating microglial M2 polarization in epileptic rats [ 31 ]. Likewise, our laboratory also verified that sitagliptin (a DPP4 inhibitor) reduced the KA-induced activation of the NF-κB signaling pathway and suppressed the inflammatory response mediated by microglia in epilepsy [ 56 ]. Here, we found that PAP-1 inhibited the NF-κB signaling pathway, resulting in attenuation of both microglial activation and epilepsy severity.…”

CD11c+ microglia promote white matter repair after ischemic stroke

“…Disease associated microglia (DAM) in neurodegenerative disease were CD11c positive, which participated in lipid metabolism and phagocytic pathways. DAM were considered to have the potential to restrict neurodegeneration [ 23 , 29 , 30 ]. Oligodendrocyte-supportive genes such as Spp1 and Igf1 were abundant in CD11c + microglia [ 31 ].…”

Sitagliptin attenuates Porphyromonas gingivalis virulence and inflammatory response in macrophage on titanium

“…Sitagliptin, the first dipeptidyl-peptidase (DPP)-4 inhibitor, was approved and widely used as a glucose-lowering intervention for patients with type 2 diabetes [14]. Recently, more studies have reported the potential therapeutic effect of sitagliptin on other diseases including epilepsy, genital infections and COVID-19 [15][16][17]. Since studies have shown that DPP-4 is also expressed on the surface of macrophages [18,19], sitagliptin may have an influence on the biological function of macrophages, thus regulating the inflammatory diseases in which macrophage involved.…”