Presenting Author:

Hadijat Makinde, Ph.D.

Principal Investigator:

Steven Schwulst, M.D.

Department:

Surgery

Keywords:

Traumatic brain injury, neutrophils, monocytes.

Location:

Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital

B178 - Basic Science Women's Health Research

Effects of monocytes on neutrophil infiltration in acute TBI

Traumatic brain injury (TBI) affect military personnel on the battlefield as well as athletes. Now that combat positions have been open to women in the military and more women are getting involved in professional sports, it is imperative to understand how this pathological condition affects women. In TBI neutrophils constitute the majority of the early infiltrate into the injured brain and are capable of worsening outcomes. Since multiple studies have implicated monocytes in the infiltration of neutrophils in multiple inflamed tissues, we hypothesized that monocytes drive the recruitment of neutrophils into the injured brain after TBI. There are two major monocyte subsets, CCR2+ classical monocytes and CX3CR1+ nonclassical monocytes. To test our hypothesis, monocytes populations were depleted to determine if neutrophil recruitment could be prevented after TBI. Global monocyte depletion was achieved via i.v. injection of clodronate-encapsulated liposomes into male C57BL/6 mice. Classical monocyte depletion was induced by i.v. injection of an anti-CCR2 mAb into male C57BL/6 mice. Lastly, CX3CR1-/- mice have reduced nonclassical monocyte counts, but normal neutrophil counts compared to control CX3CR1+/- mice, and thus were used to evaluate the role of nonclassical monocytes. Depletions were performed 24 hours prior to TBI. Brains were harvested 24 hours post TBI and infiltrating leukocyte subsets were identified. None of the depletion methods affected the circulating neutrophil population. Global monocyte depletion with clodronate resulted in abrogation of neutrophil infiltration into the injured brain. Surprisingly, targeted depletion of CCR2+ classical monocytes had no effect on neutrophil infiltration into the injured brain. Strikingly, however, CX3CR1-/- mice show significantly reduced neutrophil infiltration into the brain compared to CX3CR1+/- control mice following TBI. Our findings elucidate a critical role for nonclassical monocytes in the pathology of TBI, as they are essential for the recruitment of the deleterious neutrophil population to the injured brain after TBI. These data indicate that targeted depletion of individual monocytic subtypes may be a novel therapeutic intervention in the treatment of TBI.