Deficiency of the negative immune regulator B7-H1 enhances inflammation and neuropathic pain after chronic constriction injury of mouse sciatic nerve.
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 (TNFalpha) 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, TNFalpha and MCP-1 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 CCI 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.
Uçeyler
Nurcan
N
Department of Neurology, University of Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany.
Göbel
Kerstin
K
Meuth
Sven G
SG
Ortler
Sonja
S
Stoll
Guido
G
Sommer
Claudia
C
Wiendl
Heinz
H
Kleinschnitz
Christoph
C
D000704:Analysis of Variance; D000818:Animals; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D039481:CD11b Antigen / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D003250:Constriction; D005786:Gene Expression Regulation / Q000235:genetics*; D006930:Hyperalgesia / Q000209:etiology / Q000235:genetics; D016753:Interleukin-10 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000502:physiology; D010455:Peptides / Q000172:deficiency*; D010812:Physical Stimulation / Q000379:methods; D020426:Sciatic Neuropathy / Q000276:immunology* / Q000378:metabolism* / Q000503:physiopathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D039481:CD11b Antigen; C491768:Ccl2 protein, mouse; C498919:Cd274 protein, mouse; D018932:Chemokine CCL2; D008562:Membrane Glycoproteins; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10