Activation of Myeloid TLR4 Mediates T Lymphocyte Polarization after Traumatic Brain Injury

• Published in: The Journal of immunology (1950) 2017-05, Vol.198 (9), p.3615-3626
• Main Authors: Braun, Molly, Vaibhav, Kumar, Saad, Nancy, Fatima, Sumbul, Brann, Darrell W, Vender, John R, Wang, Lei P, Hoda, Md Nasrul, Baban, Babak, Dhandapani, Krishnan M
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; Adoptive Transfer; Animals; Bone marrow; Brain; Brain Injuries, Traumatic - immunology; Cell activation; Cell Differentiation - genetics; Cell Movement - genetics; Cell proliferation; Cell Proliferation - genetics; Cells, Cultured; Central nervous system; Coculture Techniques; Disease Models, Animal; Effector cells; Helper cells; Humans; Immune response; Immune system; Immunoregulation; Inflammation; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - physiology; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Mutant Strains; Monocytes; Mutation - genetics; Phenotype; Polarization; Public health; Rodents; Stimulators; Th1 Cells - immunology; Th17 Cells - immunology; TLR4 protein; Toll-Like Receptor 4 - genetics; Toll-like receptors; Traumatic brain injury
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1601948

Traumatic brain injury (TBI) is a major public health issue, producing significant patient mortality and poor long-term outcomes. Increasing evidence suggests an important, yet poorly defined, role for the immune system in the development of secondary neurologic injury over the days and weeks following a TBI. In this study, we tested the hypothesis that peripheral macrophage infiltration initiates long-lasting adaptive immune responses after TBI. Using a murine controlled cortical impact model, we used adoptive transfer, transgenic, and bone marrow chimera approaches to show increased infiltration and proinflammatory (classically activated [M1]) polarization of macrophages for up to 3 wk post-TBI. Monocytes purified from the injured brain stimulated the proliferation of naive T lymphocytes, enhanced the polarization of T effector cells (T 1/T 17), and decreased the production of regulatory T cells in an MLR. Similarly, elevated T effector cell polarization within blood and brain tissue was attenuated by myeloid cell depletion after TBI. Functionally, C3H/HeJ (TLR4 mutant) mice reversed M1 macrophage and T 1/T 17 polarization after TBI compared with C3H/OuJ (wild-type) mice. Moreover, brain monocytes isolated from C3H/HeJ mice were less potent stimulators of T lymphocyte proliferation and T 1/T 17 polarization compared with C3H/OuJ monocytes. Taken together, our data implicate TLR4-dependent, M1 macrophage trafficking/polarization into the CNS as a key mechanistic link between acute TBI and long-term, adaptive immune responses.