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

• Published in: Laboratory investigation Vol. 101; no. 10; pp. 1341 - 1352
• Main Authors: Kan, Hung-Wei, Chang, Chin-Hong, Chang, Ying-Shuang, Ko, Yi-Ting, Hsieh, Yu-Lin
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.10.2021; Nature Publishing Group US; Nature Publishing Group
• Subjects: 13/51; 14/28; 631/378/1689/2610; 631/378/87; 64/60; 692/617/375/1692; Activating transcription factor 3; Activating Transcription Factor 3 - genetics; Animals; Catalase; Cellular stress response; CLEC5A protein; Cytokines; Cytokines - metabolism; Diabetes; Diabetes mellitus; Diabetic Neuropathies - genetics; Diabetic Neuropathies - metabolism; Diabetic Neuropathies - physiopathology; Diabetic neuropathy; Endoplasmic reticulum; Endoplasmic Reticulum Stress - genetics; Enlargement; Heme; Heme oxygenase (decyclizing); Inflammation; Inflammatory response; Inositol; Laboratory Medicine; Lectins; Lectins, C-Type - genetics; Loss of Function Mutation - genetics; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Oxygenase; Pathology; Peripheral neuropathy; Polyadenylation; Proteins; Reactive oxygen species; Reactive Oxygen Species - metabolism; Receptors, Cell Surface - genetics; Stress; Superoxide dismutase; Transcription factors
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/s41374-021-00630-5

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 1α and phosphorylated eukaryotic initiation factor 2α 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.