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.

Prohibitin 1 is essential to preserve mitochondria and myelin integrity in Schwann cells.

“…A common feature of peripheral neuropathies is the presence of macrophages, which in ltrate the nerves to phagocytize myelin and cellular debris. In some occasions, macrophages can be involved with the initiation of peripheral neuropathies and cause demyelination 19 . Thus, we asked if macrophages were present in the nerves of Phb1-SCKO mice before demyelination.…”

Deciphering immune mechanisms in chronic inflammatory demyelinating polyneuropathies

“…Consistent with a pathogenic role for macrophages, depletion of phagocytic cells in NOD. Aire GW/+ mice protected mice from neuropathy development (61). In addition, macrophages participate in the autoimmune response through secretion of proinflammatory cytokines, direct destruction of target cells, and by presentation of antigens.…”

“…In addition to nerve regeneration, Schwann cells may also control immune cell chemotaxis into the PNS. With the onset of immune cell infiltration, Schwann cells in NOD.Aire GW/+ mice and patients with CIDP upregulate expression of the extracellular matrix protein periostin (POSTN) (61). POSTN expression promotes autoimmune destruction by increasing chemotaxis of pathogenic macrophages into the affected nerve, as Postn deficiency in NOD.Aire GW/+ mice slowed disease onset and decreased macrophage infiltration.…”

Immunohistochemical analysis of periostin in the hearts of Lewis rats with experimental autoimmune myocarditis

“…Although periostin has been implicated in various autoimmune diseases including peripheral polyneuropathy and myocardial infarction of mice [2,6], this is the first study to…”

“…Although periostin has been implicated in various autoimmune diseases including peripheral polyneuropathy and myocardial infarction of mice [ 2 , 6 ], this is the first study to show that periostin is upregulated in the hearts of EAM-induced rats, which model human myocarditis. Moreover, we found that periostin and αSMA, both of which are secreted by fibroblasts, were co-localized in the hearts of EAM-induced animals.…”