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 Article has an altmetric score of 2

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 2

Postn is expressed by Schwann cells.

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Postn is expressed by Schwann cells. Histochemistry for β-gal using X-g...
Histochemistry for β-gal using X-gal was performed on sciatic nerves from NOD.WT Postnlacz/+ mice (WT, n = 4) and NOD.AireGW/+ PostnlacZ/+ mice (n = 3) as well as from NOD.SCID PostnlacZ/+ (PostnlacZ/+) reporter mice without (n = 4) or with (n = 8) NOD.AireGW/+ (AireGW/+) splenocyte AT. (A) Macroscopic view of sciatic nerve cross sections. The perineurium of WT and NOD.SCID PostnlacZ/+ nerves was X-gal positive (arrowheads); the endoneurium (E) was also X-gal positive in NOD.AireGW/+ PostnlacZ/+ and NOD.SCID PostnlacZ/+ mice that underwent AT. Original magnification, ×4.5. (B) Semithin sections were stained with paraphenylenediamine. X-gal crystals are blue, and some large clusters are indicated with arrowheads in a region with reduced myelinated axon density. Original magnification, ×100. (C–E) EM images. Arrowheads indicate X-gal crystals, which are electron dense; asterisks indicate axons. X-gal crystals were found in promyelinating (C), nonmyelinating (D), and myelinating (E) Schwann cells. Scale bars: 2 μm (C and E) and 500 nm (D). (F) Postn expression relative to cyclophilin, measured by qRT-PCR. RNA was isolated from whole sciatic nerves from NOD.WT mice, CD11b+ or CD3+ cells enriched from NOD.AireGW/+ neuropathic mice, or p75+ Schwann cells purified from sciatic nerves from WT and affected NOD.AireGW/+ neuropathic mice. Each dot in F represents an individual mouse. (G) Immunofluorescence staining of S100B (green) and POSTN (red) in CIDP patients’ biopsy samples. Scale bar: 20 μm. (H) HSCs were cultured with NRG1, TGF-β, or both NRG1 and TGF-β. POSTN expression was measured by qRT-PCR. Each dot in H represents an individual well. **P < 0.005 and ***P < 0.0005, by 1-way ANOVA with multiple comparisons test.