Interactions between hemopoietically derived TNF and central nervous system-resident glial chemokines underlie initiation of autoimmune inflammation in the brain.
Tumor necrosis factor is a proinflammatory cytokine that induces directly many of the components required for inflammation to proceed rapidly. We show in this study that the interplay between TNF and chemokines, now recognized to be essential for normal secondary lymphoid tissue development, is also a feature of CNS inflammation, and that the two apparently dissimilar biological processes share many properties. Thus, induction of seven chemokines, including T cell activation gene 3 (TCA3), monocyte chemoattractant protein-1, and IFN-gamma-inducible protein-10 within the CNS during experimental autoimmune encephalomyelitis fails to occur early in the inflammatory process in TNF-deficient mice, despite local expression of monokines and IFN-gamma. The critical source of TNF in CNS inflammation is the infiltrating hemopoietic cell, and, in its absence, chemokine expression by irradiation-resistant CNS-resident cells fails. The CCR8 ligand, TCA3, is shown to be produced predominantly by resident microglia of the CNS in response to TNF. Using CCR8(-/-) mice, evidence is provided that TCA3-CCR8 interactions contribute to rapid-onset CNS inflammation. Thus, through TNF production, the hemopoietic compartment initiates the signals for its own movement into tissues, although the tissue ultimately defines the nature of that movement. Chemokines are a major, although not exclusive, mechanism by which tissues regulate leukocyte movement in response to TNF.
Murphy
Craig A
CA
Department of Immunology, DNAX Research, Palo Alto, CA 94304-1104, USA.
Hoek
Robert M
RM
Wiekowski
Maria T
MT
Lira
Sergio A
SA
Sedgwick
Jonathon D
JD
D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D054402:Chemokine CCL1; D018925:Chemokines / Q000096:biosynthesis; D019742:Chemokines, CC; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D006023:Glycoproteins / Q000008:administration & dosage / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016014:Linear Models; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D018448:Models, Immunological; D063308:Myelin-Oligodendrocyte Glycoprotein; D009457:Neuroglia / Q000276:immunology* / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D054401:Receptors, CCR8; D019707:Receptors, Chemokine / Q000378:metabolism; D013116:Spinal Cord / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C065971:CCL1 protein, human; C103330:CCR8 protein, human; C489319:Ccr8 protein, mouse; D054402:Chemokine CCL1; D018925:Chemokines; D019742:Chemokines, CC; D016207:Cytokines; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D054401:Receptors, CCR8; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; C445081:myelin oligodendrocyte glycoprotein (35-55)