Deficiency of the negative immune regulator B7-H1 enhances inflammation and neuropathic pain after chronic constriction injury of mouse sciatic nerve

作者：Ueceyler Nurcan; Goebel Kerstin; Meuth Sven G; Ortler Sonja; Stoll Guido; Sommer Claudia; Wiendl Heinz^*; Kleinschnitz Christoph

来源：Experimental Neurology, 2010, 222(1): 153-160.

DOI：10.1016/j.expneurol.2009.12.026

• B7-H1
• PD-L1
• CD274
• Co-inhibition
• Neuropathic pain
• T cells
• Inflammation
• Macrophages
• TNFalpha
• MCP-1

Peripheral nerve injury induces a profound local inflammatory response that involves T cells and macrophages and augments the generation of neuropathic pain. The mechanisms underlying immune cell activation or inhibition in the peripheral nervous system, however, are unknown. The co-inhibitory molecule B7-H1 (PD-L1, CD274) attenuates immune cell proliferation and cytokine production and protects from inflammation-induced tissue damage. We analyzed the temporal gene expression profile of B7-H1 and different cytokines after chronic constriction injury (CCI) of the sciatic nerve, a lesion paradigm inducing neuropathic pain, by quantitative real-time polymerase chain reaction and immunohistochemistry in B7-H1(-/-) mice and wild-type (WT) controls. B7-H1 mRNA was markedly induced in WT nerves after CCI, and macrophages could be identified as major B7-H1 source. The proinflammatory mediators tumor necrosis factor alpha (TNF alpha) and monocyte chemoattractant protein-1 (MCP-1) displayed a strong, but transient expression in degenerating nerves on day 1 after CCI in WT mice, while a biphasic expression peak on day 1 and day 28 was found in B7-H1(-/-) mice. Overall, TNF alpha and MCPA levels in B7-H1-deficient nerves dramatically exceeded those in WT controls. In contrast, induction of the anti-inflammatory cytokine interleukin(IL)-10 was restricted to WT nerves. The observation that B7-H1 deficiency enhances inflammation upon CG was further corroborated by immunohistochemistry showing increased numbers of T cells and macrophages in injured nerves from B7-H1(-/-) mice. Interestingly, mechanical hyperalgesia was more pronounced in the absence of B7-H1. Our study identifies B7-H1 as an important suppressor of the inflammatory response and neuropathic pain occurring after peripheral nerve injury.

• 出版日期2010-3