Astrocytes initiate inflammation in the injured mouse spinal cord by promoting the entry of neutrophils and inflammatory monocytes in an IL-1 receptor/MyD88-dependent fashion.
CNS injury stimulates the expression of several proinflammatory cytokines and chemokines, some of which including MCP-1 (also known as CCL2), KC (CXCL1), and MIP-2 (CXCL2) act to recruit Gr-1(+) leukocytes at lesion sites. While earlier studies have reported that neutrophils and monocytes/macrophages contribute to secondary tissue loss after spinal cord injury (SCI), recent work has shown that depletion of Gr-1(+) leukocytes compromised tissue healing and worsened functional recovery. Here, we demonstrate that astrocytes distributed throughout the spinal cord initially contribute to early neuroinflammation by rapidly synthesizing MCP-1, KC, and MIP-2, from 3 up to 12h post-SCI. Chemokine expression by astrocytes was followed by the infiltration of blood-derived immune cells, such as type I "inflammatory" monocytes and neutrophils, into the lesion site and nearby damaged areas. Interestingly, astrocytes from mice deficient in MyD88 signaling produced significantly less MCP-1 and MIP-2 and were unable to synthesize KC. Analysis of the contribution of MyD88-dependent receptors revealed that the astrocytic expression of MCP-1, KC, and MIP-2 was mediated by the IL-1 receptor (IL-1R1), and not by TLR2 or TLR4. Flow cytometry analysis of cells recovered from the spinal cord of MyD88- and IL-1R1-knockout mice confirmed the presence of significantly fewer type I "inflammatory" monocytes and the almost complete absence of neutrophils at 12h and 4days post-SCI. Together, these results indicate that MyD88/IL-1R1 signals regulate the entry of neutrophils and, to a lesser extent, type I "inflammatory" monocytes at sites of SCI.
Pineau
Isabelle
I
Department of Molecular Medicine, Laval University, Québec, Québec, Canada G1V 4G2.
Sun
Libo
L
Bastien
Dominic
D
Lacroix
Steve
S
D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism*; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D017403:In Situ Hybridization; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency*; D009504:Neutrophils / Q000276:immunology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger; D053573:Receptors, Interleukin-1 Type I / Q000172:deficiency*; D013116:Spinal Cord / Q000166:cytology; D013119:Spinal Cord Injuries / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000172:deficiency; D051197:Toll-Like Receptor 4 / Q000172:deficiency
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D053573:Receptors, Interleukin-1 Type I; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4