Schwann cells promote post-traumatic nerve inflammation and neuropathic pain through MHC class II

Hartlehnert, Maike; Derksen, Angelika; Hagenacker, Tim; D, Kindermann; Schäfers, Maria; Pawlak, Mathias; Kieseier, Bernd C.; Hörste, Gerd Meyer zu

doi:10.1038/s41598-017-12744-2

Cited by 61 publications

(53 citation statements)

References 45 publications

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“…Moreover, the progressing death of ganglionic-like tumor cells and resulting axon degeneration observed in GNBs/GNs (Li & Nakagawara, 2013) In addition to their influence on tumor cells, stromal SCs also hold a considerable potential to modulate the tumor microenvironment. We identified that stromal SCs express MHC-II receptors and chemokines, and confirmed the presence of immune cells in GN sections, which is in line with the increasing reports about the immunomodulatory potential of SCs during nerve regeneration and peripheral neuropathies (Baetas-da-Cruz et al, 2009;Bergsteinsdottir et al, 1991;Hartlehnert et al, 2017;Horste et al, 2010;Martyn et al, 2019;Weiss et al, 2016;Ydens et al, 2013). Furthermore, the shared expression signature of stromal/repair SCs contained basement membrane components and ECM remodelers such as metalloproteinases and matricellular proteins.…”

Section: Schwann Cell Plasticitysupporting

confidence: 88%

Schwann cell plasticity regulates neuroblastic tumor cell differentiation via epidermal growth factor-like protein 8

Weiss

Taschner‐Mandl

Bileck

et al. 2020

Preprint

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The remarkable plasticity of Schwann cells (SCs) enables the acquisition of repair-specific functions essential for peripheral nerve regeneration. We hypothesized that this plastic potential is manifested in stromal SCs found within mostly benign-behaving peripheral neuroblastic tumors. To shed light on the cellular state and impact of stromal SCs, we performed transcriptome profiling of human ganglioneuromas and neuroblastomas, rich and poor in SC-stroma, respectively, as well as human injured nerves, rich in repair SCs. The results revealed a nerve repair-characteristic gene expression signature of stromal SCs. In turn, primary repair SCs had a pro-differentiating and anti-proliferative effect on aggressive neuroblastoma cell lines after direct and trans-well co-culture. Within the pool of secreted stromal/repair SC factors, we identified EGFL8, a matricellular protein with so far undescribed function, to induce neuronal differentiation of neuroblastoma cell lines. This study indicates that stromal SCs underwent an adaptive response to neuroblastic tumor cells and exert repairassociated functions in the microenvironment resulting in a benign tumor development.Further, SC-derived factors, such as EGFL8, may be of therapeutic value for aggressive, SCstroma poor neuroblastomas. SYNOPSISIn order to investigate the nature of stromal Schwann cells in benign peripheral neuroblastic tumors (ganglioneuromas), we compared the cellular state of stromal Schwann cells with repair-associated Schwann cells emerging in peripheral nerves after injury. • Stromal Schwann cells in ganglioneuromas and repair Schwann cells in injured nervesshare the expression of nerve repair-associated genes.• Neuroblastoma cell lines, derived from high-risk metastatic peripheral neuroblastic tumors (neuroblastomas), respond to primary repair Schwann cells and their secretome with increased neuronal differentiation and reduced proliferation. • Stromal and repair Schwann cells express the matricellular protein EGFL8, which is capable to induce neuronal differentiation of neuroblastoma cell lines in recombinant form. Human Schwann Cell Plasticity Weiss, Taschner-Mandl et al Page 4 of 48 ABBREVIATIONS SC … Schwann cell NT … peripheral neuroblastic tumor NB … neuroblastoma GNB … ganglioneuroblatoma GN … ganglioneuroma RT … room temperature IF … immunofluorescence THE PAPER EXPLAINED ProblemIn response to peripheral nerve damage, Schwann cells (SCs) are able to transform into specialized repair cells essential for nerve cell regeneration. Our previous studies indicated that this reactive/adaptive potential of human SCs is not restricted to injured nerve cells but also emerges in response to peripheral neuroblastic tumor cells. The usually benign subtypes of peripheral neuroblastic tumors, i.e. ganglioneuroblastomas and ganglioneuromas, contain neuronal differentiating tumor cells and are pervaded by various portions of stromal SCs. Of note, the amount of stromal SCs correlates with a favorable tumor behavior and increased patient survival, whereas aggre...

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Section: Schwann Cell Plasticitysupporting

confidence: 88%

Schwann cell plasticity regulates neuroblastic tumor cell differentiation via epidermal growth factor-like protein 8

Weiss

Taschner‐Mandl

Bileck

et al. 2020

Preprint

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“…Compared with CD11b -F4/80nonmacrophage cells, CD11b + F4/80 + macrophages expressed more CD80, CD86, and MHCII ( Figure 6, F-H). CD11b -F4/80non macrophage cells from sciatic nerves of NOD.Aire GW/+ mice expressed an intermediate amount of MHCII ( Figure 6H), which may reflect an upregulation of MHCII expression by other cell types such as Schwann cells (51)(52)(53). These data suggest that nerve-infiltrating macrophages are heterogeneous, expressing both M1-and M2-associated markers, and express markers of activation.…”

Section: Resultsmentioning

confidence: 91%

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

Allard¹,

Wang²,

Li³

et al. 2018

Journal of Clinical Investigation

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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.

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“…However, it remains uncertain whether these αβ T cells are CD4 + αβ T cells and even MHCIIrestricted Th cells. Recently, CD4 + cells were shown to robustly infiltrate into the injured nerves after adult mice CCI or PSNL [115,116], and the infiltration of CD4 + cells into chronically constricted sciatic nerves are dependent on MHCII specifically expressed on Schwann cells [115]. This suggests the potential infiltration of CD4 + αβ T cells and even Th cells into the injured nerves, which needs further validations.…”

Section: Classical Pathogenic Neuroimmune Interfacesmentioning

confidence: 99%

“…Hence, the injured nerves are not a necessary neuroimmune interface for αβ T cells, including possible Th cells, to initiate the development of chronic tactile allodynia after nerve injuries. This notion needs further validation via region-specific cell targeting in a different set of nerve injury models, such as CCI, in which intact peripheral axons of primary sensory neurons (PSNs) transmitting tactile allodynia are mixed with degenerating peripheral axons of axotomized PSNs [115][116][117]. However, the number of αβ T cells in the injured nerves was shown to have no correlation with the intensity of tactile allodynia after adult rat CCI to the sciatic nerve [105].…”

Section: Classical Pathogenic Neuroimmune Interfacesmentioning

confidence: 99%

MHCII-restricted T helper cells: an emerging trigger for chronic tactile allodynia after nerve injuries

Ding¹,

Luo²,

Qi³

2020

J Neuroinflammation

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Nerve injury-induced chronic pain has been an urgent problem for both public health and clinical practice. While transition to chronic pain is not an inevitable consequence of nerve injuries, the susceptibility/resilience factors and mechanisms for chronic neuropathic pain after nerve injuries still remain unknown. Current preclinical and clinical studies, with certain notable limitations, have shown that major histocompatibility complex class II-restricted T helper (Th) cells is an important trigger for nerve injury-induced chronic tactile allodynia, one of the most prevalent and intractable clinical symptoms of neuropathic pain. Moreover, the precise pathogenic neuroimmune interfaces for Th cells remain controversial, not to mention the detailed pathogenic mechanisms. In this review, depending on the biology of Th cells in a neuroimmunological perspective, we summarize what is currently known about Th cells as a trigger for chronic tactile allodynia after nerve injuries, with a focus on identifying what inconsistencies are evident. Then, we discuss how an interdisciplinary perspective would improve the understanding of Th cells as a trigger for chronic tactile allodynia after nerve injuries. Finally, we hope that the expected new findings in the near future would translate into new therapeutic strategies via targeting Th cells in the context of precision medicine to either prevent or reverse chronic neuropathic tactile allodynia.

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Schwann cells promote post-traumatic nerve inflammation and neuropathic pain through MHC class II

Cited by 61 publications

References 45 publications

Schwann cell plasticity regulates neuroblastic tumor cell differentiation via epidermal growth factor-like protein 8

Schwann cell plasticity regulates neuroblastic tumor cell differentiation via epidermal growth factor-like protein 8

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

MHCII-restricted T helper cells: an emerging trigger for chronic tactile allodynia after nerve injuries

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