Genetic loss-of-function of activating transcription factor 3 but not C-type lectin member 5A prevents diabetic peripheral neuropathy

We investigated the mediating roles of activating transcription factor 3 (ATF3), an injury marker, or C-type lectin member 5A (CLEC5A), an inflammatory response molecule, in the induction of endoplasmic reticulum (ER) stress and neuroinflammation in diabetic peripheral neuropathy in ATF3 and CLEC5A genetic knockout (aft3(-/-) and clec5a(-/-), respectively) mice. ATF3 was expressed intranuclearly and was upregulated in mice with diabetic peripheral neuropathy (DN) and clec5a(-/-) mice. The DN and clec5a(-/-) groups also exhibited neuropathic behavior, but not in the aft3(-/-) group. The upregulation profiles of cytoplasmic polyadenylation element-binding protein, a protein translation-regulating molecule, and the ER stress-related molecules of inositol-requiring enzyme 1 alpha and phosphorylated eukaryotic initiation factor 2 alpha in the DN and clec5a(-/-) groups were correlated with neuropathic behavior. Ultrastructural evidence confirmed ER stress induction and neuroinflammation, including microglial enlargement and proinflammatory cytokine release, in the DN and clec5a(-/-) mice. By contrast, the induction of ER stress and neuroinflammation did not occur in the aft3(-/-) mice. Furthermore, the mRNA of reactive oxygen species-removing enzymes such as superoxide dismutase, heme oxygenase-1, and catalase were downregulated in the DN and clec5a(-/-) groups but were not changed in the aft3(-/-) group. Taken together, the results indicate that intraneuronal ATF3, but not CLEC5A, mediates the induction of ER stress and neuroinflammation associated with diabetic neuropathy. Neuroinflammation and endoplasmic reticulum stress is a critical process that leads to diabetic peripheral neuropathy (DPN). Activating transcription factor 3 (ATF3) is a susceptible molecule, and loss-of-function of ATF3, but not C-type lectin member 5A (CLEC5A), prevents the development of neuroinflammation and ER stress. Functional blockade of ATF3 may be a potential treatment for diabetic peripheral neuropathy by inhibiting neuroinflammation and cellular stress-induced ER stress.

Automated summary

Our study revealed that intraneuronal ATF3, rather than CLEC5A, plays a crucial role in mediating endoplasmic reticulum stress and neuroinflammation associated with diabetic neuropathy. Loss-of-function of ATF3 prevented the development of neuroinflammation and ER stress, suggesting that targeting ATF3 may be a potential therapeutic strategy for diabetic peripheral neuropathy. Neuroinflammation and ER stress are key processes in the pathogenesis of diabetic peripheral neuropathy.