TY - JOUR
T1 - Activation of myeloid TLR4 Mediates T lymphocyte polarization after traumatic brain injury
AU - Braun, Molly
AU - Vaibhav, Kumar
AU - Saad, Nancy
AU - Fatima, Sumbul
AU - Brann, Darrell W.
AU - Vender, John R.
AU - Wang, Lei
AU - Hoda, MD Nasrul
AU - Baban, Babak
AU - Dhandapani, Krishnan M.
N1 - Funding Information:
National Institutes of Health (Grants NS095154 and NS084228 to K.M.D.)
Publisher Copyright:
Copyright © 2017 by The American Association of Immunologists, Inc.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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 (TH1/TH17), 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 TH1/TH17 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 TH1/TH17 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.
AB - 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 (TH1/TH17), 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 TH1/TH17 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 TH1/TH17 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.
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U2 - 10.4049/jimmunol.1601948
DO - 10.4049/jimmunol.1601948
M3 - Article
C2 - 28341672
AN - SCOPUS:85018491618
SN - 0022-1767
VL - 198
SP - 3615
EP - 3626
JO - Journal of Immunology
JF - Journal of Immunology
IS - 9
ER -