Schwann cell–derived periostin promotes autoimmune peripheral polyneuropathy via macrophage recruitment
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
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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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 6

Macrophages promote peripheral neuropathy.

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Macrophages promote peripheral neuropathy. (A–G) RNA was isolated from t...
(A–G) RNA was isolated from the sciatic nerves of NOD.WT (WT) mice and from CD3–CD11b+ enriched macrophages from the sciatic nerves of NOD.AireGW/+ neuropathic mice. Cxcl9 (A), Cxcl10 (B), Tnfa (C), Arg (D), and Tgfb (E) expression relative to cyclophilin was measured by qRT-PCR. (F–H) Sciatic nerves from NOD or NOD.AireGW/+ neuropathic mice were digested and stained for flow cytometric analysis. Representative histograms showing CD80+ (F), CD86+ (G), and MHCII+ (H) expression on macrophages and nonmacrophages from NOD or NOD.AireGW/+ neuropathic mice. (I) Macrophages were skewed toward an M1 or M2 phenotype prior to inclusion in a Transwell migration assay; 100 ng/ml POSTN was used in the bottom chamber. All values are represented as the fold change compared with media alone. (J–N) NOD.SCID recipients of NOD.AireGW/+ splenocytes were treated with vehicle or clodronate-containing liposomes weekly starting 5 weeks (arrow) after AT; nerve conductions were done at 10 weeks (dotted line in J). (J) Neuropathy incidence curve shows that fewer clodronate-treated mice developed neuropathy. (K) Representative EMG CMAPs from untreated NOD.SCID mice as well as post-AT NOD.SCID mice treated with vehicle or clodronate liposomes (note the difference in the scale of the y axis: 5 vs. 20 mV). Compared with vehicle, clodronate significantly reduced the CMAP peak amplitudes (L), CMAP durations (M), and conduction velocities (N). Each dot represents an individual mouse. *P < 0.05, **P < 0.005, ***P < 0.0005, and ****P < 0.0001, by 2-tailed t test with Welch’s correction (A–E), log-rank test (J), or ordinary 1-way ANOVA with Tukey’s post hoc test for multiple comparisons (L–N). max, maximum.