Autophagy and Barrier Disruption in Patients with Complex Regional Pain Syndrome

The Complex Regional Pain Syndrome (CRPS) significantly impairs the quality of life of patients. It is characterized by a complex of symptoms indicating disturbances of the trophic, vascular, and somatosensory systems. In our previous study, a deficiency of miRNA-223 in blood exosomes was detected. It has been described that such a deficiency impairs autophagy. Additionally, individuals with edema, indicating barrier dysfunction, showed particularly low miRNA-223 levels. In this dissertation project, CRPS patients with low miRNA-223 were examined for autophagy disorders. Additionally, the barrier integrity formed by tight junction proteins and changes in trophicity, vascular supply, and the somatosensory system were analyzed. For this purpose, we investigated a series of autophagy proteins in the blood plasma of individuals with miRNA-223 deficiency. Skin samples were also taken from participants in the “ResolveCRPS” study. These samples were used for the analysis of mRNA and immunofluorescence of selected tight junction proteins, as well as for the examination of skin morphology, mechanoreceptors, and blood vessels. Our screening tests showed no general autophagy deficiency. However, elevated ATG16L1 levels were observed in “non-resolving” CRPS patients, correlating with exosomal miRNA-223. Furthermore, we observed a deficiency in claudin-19 mRNA gene expression in ipsilateral skin biopsies. Despite the use of new semi-automated analysis methods for tight junction proteins, no impairment of claudin-19 protein expression was observed. Morphological analysis revealed a bilateral reduction in Meissner corpuscles and blood vessels in CRPS skin biopsies. Overall, our results indicate impaired myelin barrier integrity as well as bilateral deficiency in Meissner corpuscles and papillary blood vessels. These findings are consistent with previous preclinical studies and morphological observations from biopsies of amputated limbs. The bilateral changes in skin morphology could represent a predisposition for CRPS. Future studies should validate our findings, evaluate the potential of Claudin-19 as a new therapeutic target, and investigate the effectiveness of skin biopsies in identifying at-risk patients.