Activation of Myeloid TLR4 Mediates T Lymphocyte Polarization after Traumatic Brain Injury.
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.
Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912.
Molly
M
Braun
Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912.|Department of Medical Laboratory, Imaging, and Radiological Sciences, College of Allied Health Sciences, Augusta University, Augusta, GA 30912.
Kumar
K
Vaibhav
Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA 30912.
Nancy
N
Saad
Department of Medical Laboratory, Imaging, and Radiological Sciences, College of Allied Health Sciences, Augusta University, Augusta, GA 30912.|Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA 30912.
Sumbul
S
Fatima
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912.|Charlie Norwood VA Medical Center, Augusta, GA 30912.
Darrell W
DW
Brann
Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912.
John R
JR
Vender
Department of Psychiatry, Medical College of Georgia, Augusta University, Augusta, GA 30912; and.
Lei P
LP
Wang
Department of Medical Laboratory, Imaging, and Radiological Sciences, College of Allied Health Sciences, Augusta University, Augusta, GA 30912.|Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA 30912.|Charlie Norwood VA Medical Center, Augusta, GA 30912.
Md Nasrul
MN
Hoda
Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA 30912.|Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA 30912.|Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA 30912.
Babak
B
Baban
Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912; kdhandapani@augusta.edu.|Charlie Norwood VA Medical Center, Augusta, GA 30912.
Krishnan M
KM
Dhandapani
D056704:Adaptive Immunity; D019264:Adoptive Transfer; D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics*
C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4