Interleukin-6 promotes microtubule stability in axons via Stat3 protein–protein interactions
Lauren K. Wareham,
Franklin D. Echevarria,
Jennifer L. Sousa,
Danielle O. Konlian,
Gabrielle Dallas,
Cathryn R. Formichella,
Priya Sankaran,
Peter J. Goralski,
Jenna R. Gustafson,
Rebecca M. Sappington
Affiliations
Lauren K. Wareham
Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Franklin D. Echevarria
Neuroscience Graduate Program, Vanderbilt University, Nashville, TN 37232, USA
Jennifer L. Sousa
Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Atrium Health Wake Forest Baptist Medical Center, 1 Medical Center Boulevard, Winston-Salem, NC 27157, USA
Danielle O. Konlian
Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Atrium Health Wake Forest Baptist Medical Center, 1 Medical Center Boulevard, Winston-Salem, NC 27157, USA
Gabrielle Dallas
Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Cathryn R. Formichella
Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Priya Sankaran
Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Peter J. Goralski
Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Atrium Health Wake Forest Baptist Medical Center, 1 Medical Center Boulevard, Winston-Salem, NC 27157, USA
Jenna R. Gustafson
Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Atrium Health Wake Forest Baptist Medical Center, 1 Medical Center Boulevard, Winston-Salem, NC 27157, USA
Rebecca M. Sappington
Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Atrium Health Wake Forest Baptist Medical Center, 1 Medical Center Boulevard, Winston-Salem, NC 27157, USA; Department of Ophthalmology, Wake Forest School of Medicine, Winston-Salem, NC 27106, USA; Corresponding author
Summary: The interleukin-6 (IL-6) family of cytokines and its downstream effector, STAT3, are important mediators of neuronal health, repair, and disease throughout the CNS, including the visual system. Here, we elucidate a transcription-independent mechanism for the neuropoietic activities of IL-6 related to axon development, regeneration, and repair. We examined the outcome of IL-6 deficiency on structure and function of retinal ganglion cell (RGC) axons, which form the optic projection. We found that IL-6 deficiency substantially delays anterograde axon transport in vivo. The reduced rate of axon transport is accompanied by changes in morphology, structure, and post-translational modification of microtubules. In vivo and in vitro studies in mice and swine revealed that IL-6-dependent microtubule phenotypes arise from protein-protein interactions between STAT3 and stathmin. As in tumor cells and T cells, this STAT3-stathmin interaction stabilizes microtubules in RGCs. Thus, this IL-6-STAT3-dependent mechanism for axon architecture is likely a fundamental mechanism for microtubule stability systemically.
