Tenascin-R Plays a Role in Neuroprotection via Its Distinct Domains That Coordinate to Modulate the Microglia Function

Hong Liao,Wen-Yu Bu,Ting-Hua Wang,Sohail Ahmed,Zhi-Cheng Xiao

doi:10.1074/jbc.m412730200

Hong Liao, Wen-Yu Bu + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m412730200

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Abstract

Microglia are one of the main cell types activated by brain injury. In the present study, we have investigated how domains of the extracellular matrix molecule tenascin-R (TN-R) modulate microglia function. We found that epidermal growth factor-like repeats inhibited adhesion and migration of microglia via a protein kinase A-dependent mechanism. In contrast, fibronectin 6-8 repeats promoted adhesion and migration of the primary microglia via a protein kinase C-dependent mechanism. Both domains of TN-R induced an up-regulation in the secretion of cytokines, such as chemokine-induced cytokine 3 and tumor neurosis factor alpha. Interestingly, epidermal growth factor-like repeats and fibronectin 6-8 induced a dramatic up-regulation in the secretion of brain-derived neurotrophic factor/transforming growth factor-beta and nerve growth factor/transforming growth factor-beta, respectively, and conditioned medium from activated microglia was able to promote neurite outgrowth of N1E-115 cells and primary cortical neurons. These results suggest that TN-R plays a role in neuroprotection through distinct domains coordinating to modulate microglia function.

Highlights

Microglia are recognized as one of main players in the response to brain and spinal cord injury because these cells are rapidly activated in response to even minor pathological changes in the central nervous system [1, 2]
TN-R comprise a cysteine-rich amino-terminal part that is involved in multimerization, a region consisting of epidermal growth factor-like repeats (EGFL), a region consisting of fibronectin type-like (FN) homologous repeats, and a fibrinogenlike domain (FG) at the carboxyl-terminus
After adhering for either 1 h (Fig. 1C, a) or 24 h (Fig. 1C, b), the number of microglia markedly increased in adherence to FN6 – 8 and FG domains and significantly reduced to EGFL domain, and there was no significant change to FN1–2 and FN3–5 domains compared with glutathione S-transferase (GST) (Fig. 1B, a–f, and C)

Summary

Introduction

Microglia are recognized as one of main players in the response to brain and spinal cord injury because these cells are rapidly activated in response to even minor pathological changes in the central nervous system [1, 2]. Epidermal growth factor-like repeats and fibronectin 6 – 8 induced a dramatic up-regulation in the secretion of brain-derived neurotrophic factor/transforming growth factor-␤ and nerve growth factor/transforming growth factor-␤, respectively, and conditioned medium from activated microglia was able to promote neurite outgrowth of N1E-115 cells and primary cortical neurons.

Results

Conclusion