ACTIVATION OF MYELOID TOLL-LIKE RECEPTOR 4 MEDIATES T-LYMPHOCYTE POLARIZATION AFTER TRAUMATIC BRAIN INJURY

• Published in: The Journal of immunology (1950) 2017-03, 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
• 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 neurological injury over the days and weeks following a TBI. Herein, 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 pro-inflammatory (M1) polarization of macrophages for up to three weeks post-TBI. Monocytes purified from the injured brain stimulated the proliferation of naïve T lymphocytes, enhanced the polarization of T effector cells (T eff : T H 1/T H 17), and decreased the production of regulatory T cells (T REG ) in a mixed lymphocyte reaction. Similarly, elevated T eff polarization within both blood and brain tissue was attenuated by myeloid cell depletion after TBI. Functionally, C3H/HeJ (TLR4 mutant) mice reversed both M1 macrophage and T H 1/T H 17 polarization after TBI, as compared to C3H/OuJ (wild-type) mice. Moreover, brain monocytes isolated from C3H/HeJ mice were less potent stimulators of T lymphocyte proliferation and T H 1/T H 17 polarization, as compared to 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.