Transcriptomic analysis of human sensory neurons in painful diabetic neuropathy reveals inflammation and neuronal loss

Author:

Hall Bradford E.,Macdonald Emma,Cassidy Margaret,Yun Sijung,Sapio Matthew R.,Ray Pradipta,Doty Megan,Nara Pranavi,Burton Michael D.,Shiers Stephanie,Ray-Chaudhury Abhik,Mannes Andrew J.,Price Theodore J.,Iadarola Michael J.,Kulkarni Ashok B.

Abstract

AbstractPathological sensations caused by peripheral painful neuropathy occurring in Type 2 diabetes mellitus (T2DM) are often described as ‘sharp’ and ‘burning’ and are commonly spontaneous in origin. Proposed etiologies implicate dysfunction of nociceptive sensory neurons in dorsal root ganglia (DRG) induced by generation of reactive oxygen species, microvascular defects, and ongoing axonal degeneration and regeneration. To investigate the molecular mechanisms contributing to diabetic pain, DRGs were acquired postmortem from patients who had been experiencing painful diabetic peripheral neuropathy (DPN) and subjected to transcriptome analyses to identify genes contributing to pathological processes and neuropathic pain. DPN occurs in distal extremities resulting in the characteristic “glove and stocking” pattern. Accordingly, the L4 and L5 DRGs, which contain the perikarya of primary afferent neurons innervating the foot, were analyzed from five DPN patients and compared with seven controls. Transcriptome analyses identified 844 differentially expressed genes. We observed increases in levels of inflammation-associated transcripts from macrophages in DPN patients that may contribute to pain hypersensitivity and, conversely, there were frequent decreases in neuronally-related genes. The elevated inflammatory gene profile and the accompanying downregulation of multiple neuronal genes provide new insights into intraganglionic pathology and mechanisms causing neuropathic pain in DPN patients with T2DM.

Funder

National Institutes of Health, USA

NIH Clinical Center

Office of Extramural Research, National Institutes of Health

National Institutes of Health

Publisher

Springer Science and Business Media LLC

Subject

Multidisciplinary

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