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 5

POSTN promotes macrophage chemotaxis via AM and AV integrins.

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POSTN promotes macrophage chemotaxis via AM and AV integrins. (A) Transw...
(A) Transwell migration assay diagram. T cells or macrophages were placed in the upper chamber of a Transwell, and POSTN was placed in the lower chamber. Following a 4-hour (T cells) or 18-hour (macrophages) culture, the number of cells in the bottom chamber was enumerated. The concentration of POSTN was varied from 50 to 1,000 ng/ml. (B) CD4+ T cells isolated from the spleens of neuropathic NOD.AireGW/+ mice were used in a Transwell migration assay as outlined in A. Each dot represents an individual mouse. (C) RAW macrophages were used in a Transwell migration assay. Each dot represents an individual well. (D) Bone marrow was isolated from NOD.AireGW/+ neuropathic mice and grown in the presence of GM-CSF for 5 days to generate bone marrow–derived macrophages, which were used in a Transwell migration assay. Each dot represents an individual mouse. (E) Sciatic nerves from neuropathic NOD.AireGW/+ mice were digested and stained for flow cytometry. A representative histogram of ITGAV expression on CD45+CD11b+F4/80+ macrophages is shown. ITGAV expression was compared with a fluorescence-minus-one (FMO) control. The number represents the frequency of events within the gate. RAW cells (F) or bone marrow–derived macrophages (G) were used in a Transwell migration assay with 100 ng/ml POSTN. IgG isotype control, anti-ITGAM (CD11b), or anti-ITGAV antibodies were included in the top chamber of the Transwell. All values are represented as the fold change compared with media alone. ****P < 0.0001. Statistical analysis was performed in R using the lm() function, where parameters were fit to each mouse as well as the difference in treatment. P values were calculated by comparing the fit of the full model to a model without a term for the difference in treatment and adjusted using Bonferroni’s correction.