Small fiber integrity and axonal pathology in the rat model of experimental autoimmune neuritis

Abstract Experimental autoimmune neuritis (EAN) is a common animal model for acute human immune-mediated polyneuropathies. Although already established in 1955, a number of pathophysiological mechanisms still remain unknown. Here, we extensively characterize EAN progression in Lewis rats, including new insights into the integrity of small nerve fibers, neuropathic pain, and macrophage activation. Acute EAN was induced with P253-78 peptide and consequently investigated using the gait analysis system CatWalk XT, electrophysiological and histopathological analyses, quantitative PCR, dorsal root ganglia outgrowth studies, as well as the von Frey hair and Hargreaves test. For the longitudinal setup, rats were sacrificed at day (d) 10 (onset), d15 (peak), d26 (recovery), and d29 (late recovery). We confirmed the classical T-cell and macrophage-driven inflammation and the primarily demyelinating nature of the EAN. The dual role of macrophages in EAN is implicated by the high number of remaining macrophages throughout disease progression. Furthermore, different subpopulations of macrophages based on Cx3-motif chemokine receptor 1 (Cx3cr1), platelet factor 4 (Pf4), and macrophage galactose -type lectin-1 (Mgl1) expression were identified. In addition, modulation of the sensory system in EAN was detected. An outgrowth of small fibers in the plantar skin at the onset and peak of the EAN was evident parallel to the development of acute hyperalgesia mediated through transient receptor potential vanilloid 1 modulation. Our data depict EAN as a primary demyelinating disease with implicated axonal damage, small unmyelinated fiber impairment throughout the disease progression course, and the pivotal role of macrophages in the effector and during the recovery stage.