Schwann cell–derived periostin promotes autoimmune peripheral polyneuropathy via macrophage recruitment
Denise E. Allard, … , Steven S. Scherer, Maureen A. Su
Denise E. Allard, … , Steven S. Scherer, Maureen A. Su
Published September 17, 2018
Citation Information: J Clin Invest. 2018;128(10):4727-4741. https://doi.org/10.1172/JCI99308.
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Research Article Autoimmunity Neuroscience

Schwann cell–derived periostin promotes autoimmune peripheral polyneuropathy via macrophage recruitment

Abstract

Chronic inflammatory demyelinating polyneuropathy (CIDP) and Guillain-Barre syndrome (GBS) are inflammatory neuropathies that affect humans and are characterized by peripheral nerve myelin destruction and macrophage-containing immune infiltrates. In contrast to the traditional view that the peripheral nerve is simply the target of autoimmunity, we report here that peripheral nerve Schwann cells exacerbate the autoimmune process through extracellular matrix (ECM) protein induction. In a spontaneous autoimmune peripheral polyneuropathy (SAPP) mouse model of inflammatory neuropathy and CIDP nerve biopsies, the ECM protein periostin (POSTN) was upregulated in affected sciatic nerves and was primarily expressed by Schwann cells. Postn deficiency delayed the onset and reduced the extent of neuropathy, as well as decreased the number of macrophages infiltrating the sciatic nerve. In an in vitro assay, POSTN promoted macrophage chemotaxis in an integrin-AM (ITGAM) and ITGAV-dependent manner. The PNS-infiltrating macrophages in SAPP-affected nerves were pathogenic, since depletion of macrophages protected against the development of neuropathy. Our findings show that Schwann cells promote macrophage infiltration by upregulating Postn and suggest that POSTN is a novel target for the treatment of macrophage-associated inflammatory neuropathies.

Authors

Denise E. Allard, Yan Wang, Jian Joel Li, Bridget Conley, Erin W. Xu, David Sailer, Caellaigh Kimpston, Rebecca Notini, Collin-Jamal Smith, Emel Koseoglu, Joshua Starmer, Xiaopei L. Zeng, James F. Howard Jr., Ahmet Hoke, Steven S. Scherer, Maureen A. Su

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Figure 3

Postn deficiency protects against neuropathy.

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Postn deficiency protects against neuropathy. NOD.SCIDPostn+/+, NOD.SCI...
NOD.SCIDPostn+/+, NOD.SCIDPostn+/–, and NOD.SCIDPostn–/– mice after AT with NOD.AireGW/+ activated splenocytes. NOD.SCID Postn–/– mice were compared with NOD.SCID Postn+/+ and NOD.SCID Postn+/– mice. (A) Neuropathy incidence curve shows the onset of clinical symptoms. Dotted line represents the time point at which mice were used in experiments (10 weeks after AT). (B) Representative CMAP traces 10 weeks after AT. The CMAP of the NOD.SCID Postn+/– nerve had a smaller amplitude and was more dispersed than that of the NOD.SCID Postn–/– nerve (note the difference in the y-axis scale: 2 vs. 20 mV). (C) Peak amplitude, (D) conduction velocity, and (E) duration of CMAPs for mice in A. Each dot represents an individual mouse. (F) Representative images of semithin sections of sciatic nerves from NOD.SCID Postn+/– (n = 8) and NOD.SCID Postn–/– (n = 3) recipients of NOD.AireGW/+ activated splenocytes. Original magnification, ×100. (G) The number of myelinated axons/1,000 μm2 was counted in cross sections of tibial nerves from NOD.SCID Postn+/– and NOD.SCID Postn–/– AT recipients. (H) EM images. Demyelinated axons (indicated by asterisks) were observed in the NOD.SCID Postn+/– nerve (n = 8), whereas the NOD.SCID Postn–/– (n = 3) nerve looked normal. Scale bar: 2 μm. (I) H&E staining of sciatic nerves. The NOD.SCID Postn+/– nerve was heavily infiltrated by hematoxylin-positive nuclei compared with the NOD.SCID Postn–/– nerve. Scale bar: 12 μm. (J) Infiltration scores were assigned as follows: 0 = no infiltration; 1 = 1%–25% of the nerve was infiltrated; 2 = 26%–50% of the nerve was infiltrated; 3 = 51%–75% of the nerve was infiltrated; 4 = 76%–100% of the nerve was infiltrated. Each dot represents an individual mouse. *P < 0.05 and **P < 0.005, by log-rank test (A), 2-tailed, unpaired t test with Welch’s correction (C–E and G), or Fisher’s exact test (J).