Lymphocyte infiltration in the injured brain: Role of proinflammatory cytokines

• Published in: Journal of neuroscience research Vol. 72; no. 6; pp. 726 - 733
• Main Authors: Raivich, Gennadij, Bohatschek, Marion, Werner, Alexander, Jones, Leonard L., Galiano, Matthias, Kloss, Christian U.A., Zhu, Xing-Zu, Pfeffer, Klaus, Liu, Zhi Qiang
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.06.2003
• Subjects: Animals; Axotomy; Brain Stem - metabolism; Brain Stem - pathology; Cell Communication - physiology; Cell Movement - physiology; cell trafficking; cytokine receptors; Cytokines - deficiency; Cytokines - genetics; Cytokines - physiology; Facial Nerve - metabolism; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Lymphocytes - metabolism; Lymphocytes - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia - pathology; neuroimmunology; Phagocytosis - physiology; Receptors, Cytokine - deficiency; Receptors, Cytokine - genetics; Receptors, Cytokine - physiology; rodents; T-lymphocytes
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/jnr.10621

Studies using mouse axotomised facial motoneuron model show a strong and highly selective entry of CD3+ lymphocytes into the affected nucleus, with a maximum at Day 14, which coincides with the peak of neuronal cell death, microglial phagocytosis, and increased synthesis of interleukin‐1 beta (IL1β), tumour necrosis factor‐alpha (TNFα) and interferon‐gamma (IFNγ). We explored the possible involvement of these cytokines during the main phase of lymphocyte recruitment into the axotomised facial motor nucleus 7–21 days after nerve cut using mice homozygously deficient for IL1 receptor type 1 (IL1R1−/−), TNF receptor type 1 (TNFR1−/−), type 2 (TNFR2−/−) and type 1 and 2 (TNFR1&2−/−), IFNγ receptor type 1 (IFNγR1−/−), and the appropriate controls for the genetic background. Transgenic deletion of IL1R1 led to a 54% decrease and that of TNFR2 to a 44% reduction in the number of CD3+ T‐cells in the axotomised facial motor nucleus, with a similar relative decrease at Day 7, 14, and 21. Deletion of TNFR1 or IFNγR1 had no significant effect. Deletion of both TNFR1 and 2 (TNFR1&2−/−) caused a somewhat stronger, 63% decrease than did TNFR2 deletion alone, but this could be due to an almost complete inhibition of neuronal cell death. No mutations seemed to inhibit aggregation of CD3+ T‐cells around glial nodules consisting of Ca‐ion binding adaptor protein‐1 (IBA1)+ phagocytotic microglia and neuronal debris. Altogether, the current data show the importance of IL1R1 and TNFR2 as the key players during the main phase of lymphocyte recruitment to the damaged part of the central nervous system. © 2003 Wiley‐Liss, Inc.