Activation of myeloid TLR4 Mediates T lymphocyte polarization after traumatic brain injury

Molly Braun, Kumar Vaibhav, Nancy Saad, Sumbul Fatima, Darrell W Brann, John R Vender, Lei Wang, MD Nasrul Hoda, Babak Baban, Krishnan Michael Dhandapani

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3615-3626
Number of pages12
JournalJournal of Immunology
Volume198
Issue number9
DOIs
StatePublished - May 1 2017

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T-Lymphocytes
Macrophages
Monocytes
Adaptive Immunity
Brain
Nervous System Trauma
Th17 Cells
Adoptive Transfer
Inbred C3H Mouse
Regulatory T-Lymphocytes
Myeloid Cells
Traumatic Brain Injury
Brain Injuries
Immune System
Public Health
Bone Marrow
Mortality

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Activation of myeloid TLR4 Mediates T lymphocyte polarization after traumatic brain injury. / Braun, Molly; Vaibhav, Kumar; Saad, Nancy; Fatima, Sumbul; Brann, Darrell W; Vender, John R; Wang, Lei; Hoda, MD Nasrul; Baban, Babak; Dhandapani, Krishnan Michael.

In: Journal of Immunology, Vol. 198, No. 9, 01.05.2017, p. 3615-3626.

Research output: Contribution to journalArticle

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