Differential role of tumor necrosis factor receptors in mouse brain inflammatory responses in cryolesion brain injury.
Tumor necrosis factor-alpha (TNF-alpha) is one of the mediators dramatically increased after traumatic brain injury that leads to the activation, proliferation, and hypertrophy of mononuclear, phagocytic cells and gliosis. Eventually, TNF-alpha can induce both apoptosis and necrosis via intracellular signaling. This cytokine exerts its functions via interaction with two receptors: type-1 receptor (TNFR1) and type-2 receptor (TNFR2). In this work, the inflammatory response after a freeze injury (cryolesion) in the cortex was studied in wild-type (WT) animals and in mice lacking TNFR1 (TNFR1 KO) or TNFR2 (TNFR2 KO). Lack of TNFR1, but not of TNFR2, significantly decreased the inflammatory response and tissue damage elicited by the cryolesion at both 3 and 7 days postlesion, with decreased gliosis, lower IL-1beta immunostaining, and a reduction of apoptosis markers. Cryolesion produced a clear induction of the proinflammatory cytokines interleukin (IL)-1alpha, IL-1beta, IL-6, and TNF-alpha; this induction was significantly lower in the TNFR1 KO mice. Host response genes (ICAM-1, A20, EB22/5, and GFAP) were also induced by the cryolesion, but to a lesser extent in TNFR1 KO mice. Lack of TNFR1 signaling also affected the expression of apoptosis/cell death-related genes (Fas, Rip, p53), matrix metalloproteinases (MMP3, MMP9, MMP12), and their inhibitors (TIMP1), suggesting a role of TNFR1 in extracellular matrix remodeling after injury. However, GDNF, NGF, and BDNF expression were not affected by TNFR1 deficiency. Overall, these results suggest that TNFR1 is involved in the early establishment of the inflammatory response and that its deficiency causes a decreased inflammatory response and tissue damage following brain injury.
Quintana
Albert
A
Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Animal Physiology Unit, Faculty of Sciences, Autonomous University of Barcelona, Bellaterra, Barcelona, Spain.
Giralt
Mercedes
M
Rojas
Santiago
S
Penkowa
Milena
M
Campbell
Iain L
IL
Hidalgo
Juan
J
Molinero
Amalia
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D003080:Cold Temperature / Q000009:adverse effects; D016207:Cytokines / Q000378:metabolism; D003714:Denervation; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D004660:Encephalitis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D017781:Genes, Immediate-Early / Q000502:physiology; D005911:Gliosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006133:Growth Substances / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D006133:Growth Substances; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1