Abstract
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.
Highlights
Diabetic peripheral neuropathy is a complicated condition caused by hyperglycemia-induced endoplasmic reticulum (ER) stress [1] and neuroinflammation, and its treatment is a clinical challenge [2]
Our previous study demonstrated that activating transcription factor 3 (ATF3) expression by the neuronal ε isoform of protein kinase determined neuropathic behavior in a mouse model of diabetic peripheral neuropathy [10]
Neuronal injury-dependent ATF3 upregulation mediated neuroinflammation and ER stress ATF3 is a susceptible intranuclear molecule associated with neuropathic manifestation in diabetic peripheral neuropathy [10], and injury-dependent ATF3 upregulation is associated with neuroinflammation [42], implying that neuroinflammation is a critical neuropathological process underlying pain development [43]
Summary
Diabetic peripheral neuropathy is a complicated condition caused by hyperglycemia-induced endoplasmic reticulum (ER) stress [1] and neuroinflammation, and its treatment is a clinical challenge [2]. Skin denervation after diabetes is correlated with neuropathic pain [3], indicating IENF densities as a predictor of diabetic peripheral neuropathy progression [4], and neuropathic behavior in diabetic patients [5,6,7]. Activating transcription factor 3 (ATF3), a potential neuronal marker under pathology, was activated on small nociceptors in concert with skin denervation [10], suggesting that ATF3 is a critical marker in addition to noxious transduction by IENF. Despite the diverse roles of ATF3 in pathology and cellular homeostasis, the cascade signal between ER stress and ATF3 in diabetic peripheral neuropathy remains elusive. Proinflammatory cytokines induce both ER stress and ATF3 upregulation [18], suggesting that diabetic peripheral neuropathy is a complicated neuropathology underlying neuroinflammation
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