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 1

Increased Postn expression in SAPP.

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Increased Postn expression in SAPP. (A–F) RNA was isolated from the scia...
(A–F) RNA was isolated from the sciatic nerves of NOD.WT (WT) and NOD.AireGW/+ neuropathic mice. Lama2 (A), Lama4 (B), Lama5 (C), Lamb1 (D), Thbs2 (E), and Postn (F) expression relative to cyclophilin was measured by qRT-PCR. Values are expressed as the fold change compared with WT. (G) POSTN expression was measured by Western blotting of sciatic nerve lysates from NOD.WT (WT) and NOD.AireGW/+ (AireGW/+) neuropathic mice. GAPDH was used as a loading control. Each lane represents an individual mouse. (H) Densitometric analysis of the Western blot in G. (I) POSTN immunohistochemical staining of sciatic nerves from WT mice, neuropathic NOD.AireGW/+ mice, neuropathic SCID recipients of NOD.AireGW/+ splenocytes, and neuropathic SCID recipients of P0T splenocytes. Note that POSTN immunoreactivity was mostly found in the perineurium (arrowheads) of NOD.WT (WT) nerves, whereas the endoneurium was diffusively positive in nerves from NOD.AireGW/+ mice, SCID recipients of NOD.AireGW/+ splenocyte AT, and SCID recipients of NOD.POT splenocyte AT. Scale bar: 180 μm. (J) Immunofluorescence staining of biopsy samples from patients with axonal neuropathy or CIDP. Increased endoneurial POSTN immunoreactivity was observed in the CIDP sample. Scale bar: 200 μm. (A–F and H) Each dot represents an individual animal. **P < 0.005 and ****P < 0.0001, by 2-tailed, unpaired t test. Individuals values and means are shown.