Satellite glia as a critical component of diabetic neuropathy: Role of lipocalin‐2 and pyruvate dehydrogenase kinase‐2 axis in the dorsal root ganglion

Abstract

Diabetic peripheral neuropathy (DPN) is a common complication of uncontrolled diabetes. The pathogenesis of DPN is associated with chronic inflammation in dorsal root ganglion (DRG), eventually causing structural and functional changes. Studies on DPN have primarily focused on neuronal component, and there is limited knowledge about the role of satellite glial cells (SGCs), although they completely enclose neuronal soma in DRG. Lipocalin‐2 (LCN2) is a pro‐inflammatory acute‐phase protein found in high levels in diverse neuroinflammatory and metabolic disorders. In diabetic DRG, the expression of LCN2 was increased exclusively in the SGCs. This upregulation of LCN2 in SGCs correlated with increased inflammatory responses in DRG and sciatic nerve. Furthermore, diabetes‐induced inflammation and morphological changes in DRG, as well as sciatic nerve, were attenuated in Lcn2 knockout (KO) mice. Lcn2 gene ablation also ameliorated neuropathy phenotype as determined by nerve conduction velocity and intraepidermal nerve fiber density. Mechanistically, studies using specific gene KO mice, adenovirus‐mediated gene overexpression strategy, and primary cultures of DRG SGCs and neurons have demonstrated that LCN2 enhances the expression of mitochondrial gate‐keeping regulator pyruvate dehydrogenase kinase‐2 (PDK2) through PPARβ/δ, thereby inhibiting pyruvate dehydrogenase activity and increasing production of glycolytic end product lactic acid in DRG SGCs and neurons of diabetic mice. Collectively, our findings reveal a crucial role of glial LCN2‐PPARβ/δ‐PDK2‐lactic acid axis in progression of DPN. Our results establish a link between pro‐inflammatory LCN2 and glycolytic PDK2 in DRG SGCs and neurons and propose a novel glia‐based mechanism and drug target for therapy of DPN. Main Points Diabetes upregulates LCN2 in satellite glia, which in turn increases pyruvate dehydrogenase kinase‐2 (PDK2) expression and lactic acid production in dorsal root ganglia (DRG). Glial LCN2‐PDK2‐lactic acid axis in DRG plays a crucial role in the pathogenesis of diabetic neuropathy.

The association of elevated serum lipocalin 2 levels with diabetic peripheral neuropathy in type 2 diabetes

“…Coincident with our observations, a most recent study on DPN in mice model has revealed that LCN2 expressions in both DRG and sciatic nerve increase significantly in DPN mice ( 12 ). Under the conditions of diabetes, LCN2 from satellite glial cells mediates macrophage infiltration into DRG, stimulates the release of inflammatory cytokines such as tumor necrosis factor-α, and enhances neuronal inflammatory response.…”

“…For neurological diseases, the role of LCN2 has been implicated in diabetic encephalopathy and some other neurological diseases in animal models with metabolic disturbance ( 10 , 11 ). Most recently, a report by Bhusal et al indicated that glial-derived LCN2 played an important role in the pathogenesis of DPN via PDK2-lactic acid axis in the dorsal root ganglion (DRG) in mice model ( 12 ). Nevertheless, the relationship between LCN2 and DPN in humans remains unclear.…”

The Association of Elevated Serum Lipocalin-2 Levels With Diabetic Peripheral Neuropathy in Type 2 Diabetes

“…Coincident with our observations, a most recent study on DPN in mice model has revealed that LCN2 expressions in both DRG and sciatic nerve increase signi cantly in DPN mice [12]. Under the conditions of diabetes, LCN2 from satellite glial cells mediates macrophage in ltration into DRG, stimulates the, release of in ammatory cytokines such as tumor necrosis factor-α, and enhances neuronal in ammatory response.…”

Discrepancy in the Usage of GFAP as a Marker of Satellite Glial Cell Reactivity

“…This leads to the conclusion that the generalized link between GFAP and gliosis that we demonstrate here might not always be the case. The literature on mouse models shows increased GFAP expression in models of type 1 diabetes [6,39], chemotherapy [10], and inflammation [3,4,37,38]. However, in stark contrast to rat models we were able to locate very few papers utilizing mouse models of nerve injury with simultaneous analysis of GFAP regulation in the DRGs.…”