Age and facial nerve axotomy-induced T cell trafficking: relation to microglial and motor neuron status.

Following peripheral axotomy of the facial nerve in mice, T lymphocytes cross the blood-brain-barrier (BBB) into the central nervous system (CNS), where they home to the neuronal cell bodies of origin in the facial motor nucleus (FMN) and act in concert with microglial cells to support the injured motor neurons. Several lines of evidence suggested normal aging may alter the injury-related responses of T cells, microglia, and motor neurons in this model. In this study, we therefore sought to test the hypothesis that compared to 8-week-old mice (young adult), 52-week-old mice (advanced middle age) would exhibit more neuronal damage and increased T cell trafficking into the injured FMN following facial nerve resection. Comparison of 8- and 52-week-old mice at 7, 14, 21, and 28 days post-resection of the facial nerve, confirmed our hypothesis that age influences the kinetics of CD3(+) T lymphocyte trafficking in the axotomized FMN. The peak T cell response was significantly higher, occurred later, and remained elevated longer in the injured FMN of mice in the 52 week age group. Although the kinetics of motor neuron death (identified by quantifying CD11b(+) perineuronal microglial phagocytic clusters engulfing the dead neurons at 7, 14, 21, and 28 days post-resection) differed between the age groups, motor neuron profile counts at day 28 showed that levels of cumulative motor neuron loss did not differ between the age groups. Compared to 8-week-old mice, however, there was small reduction in the mean cell size of the surviving motor neurons in the 52 week age group. Since T lymphocyte function decreases with normal aging, it will be important to determine if increased T cell trafficking into the injured CNS is a compensatory response to the decreased function of older T cells, and if these and related neuroimmunological changes are more pronounced in mice in the late stages of the life cycle.

Interleukin-2 deficiency-induced T cell autoimmunity in the mouse brain.

Interleukin-2 (IL-2) has been implicated in the pathogenesis of neurodevelopmental and neurodegenerative disorders. Studies from our lab have shown that adult IL-2 knockout (KO) mice exhibit septohippocampal pathology and related behavioral deficits. Compared to IL-2 wild-type (WT) mice, IL-2 KO mice have a marked and selective loss of septal cholinergic neurons that occurs between the third postnatal week and adulthood. Given that the development of septal neurons is completed by embryonic day 17 and that IL-2 KO mice exhibit peripheral autoimmunity that develops progressively post-weaning, our data and others led us to postulate that the loss of septal neurons in adult IL-2 KO mice is due to selective autoimmune neurodegeneration that coincides with increasing levels of peripheral autoimmunity. Thus, the present study tested the hypotheses: (1) that T cells selectively target the septum, and; (2) that T lymphocyte infiltration to the septum would correlate with peripheral autoimmune disease. We quantified CD3(+) T cells in the septum, hippocampus, and cerebellum of IL-2 KO and IL-2 WT mice at ages ranging from 2 to 14 weeks. T cells infiltrated the brains of IL-2 deficient mice, but were not selective for the septum. Brain T lymphocyte levels in IL-2 KO mice correlated positively with the degree of peripheral autoimmunity. We did not detect CD19(+) B lymphocytes, IgG-positive lymphocytes or IgG deposition indicative of autoantibodies in the brains of IL-2 KO mice. Further study is needed to understand how IL-2 deficiency-induced autoimmune T lymphocytes interact with endogenous brain cells to alter function and promote disease.

Stat3 regulates genes common to both wound healing and cancer.

Wound healing and cancer are both characterized by cell proliferation, remodeling of extracellular matrix, cell invasion and migration, new blood vessel formation, and modulation of blood coagulation. The mechanisms that link wound healing and cancer are poorly understood. We report here that Stat3, a common signaling mechanism involved in oncogenesis and tissue injury, regulates a common set of genes involved in wound healing and cancer. Using oligonucleotide gene arrays and quantitative real-time PCR, we evaluated changes in global gene expression resulting from expression of Stat3 in lung epithelial cells. We report here previously uncharacterized genes induced by Stat3 implicated in signaling pathways common to both wound healing and cancer including cell invasion and migration, angiogenesis, modulation of coagulation, and repression of interferon-inducible genes. Consistent with these results, we found increased Stat3 activity associated with wound healing in chronically inflamed mouse lungs and increased Stat3 activity was identified at the leading edge of lung tumors invading adjacent nontumor stroma. These findings provide a molecular basis for understanding cancer as a deregulation of normal wound healing processes.