Traumatic Brain Injury (TBI) Causes Alterations in Myeloid Cell Function: Role of Sex Differences and Lung Infection on Overall Outcomes following TBI

Abstract

Traumatic brain injury (TBI) is a major cause of morbidity and mortality. Males are nearly 3-times more likely to die from brain injury than females. However, the impact of sex differences in relation to clinical outcomes following TBI is conflicting. Recent studies report that men have an increased risk for lung infection after TBI. Importantly, hospitalized severely injured TBI patients have nosocomial infection rates of 50%. Acute-onset pneumonia represents 30-50% of infections after more severe TBI, leading to increased deaths and disability. The goal of this work was to investigate the role of sex differences and lung infection on overall outcomes following TBI. In a well-characterized murine TBI model, there are increased numbers of infiltrating myeloid cells in male brains as compared to females following injury, correlating with poorer neurological outcomes. However, myeloid cells and microglia in male and female animals showed a similar pattern of activation in response to brain injury- including increased pro-inflammatory cytokines (TNF-α, IL-1β), reactive oxygen species (ROS), and greater phagocytic activity. These these findings suggest that sex differences with regard to immune responses after TBI that may impact overall outcomes. We also examined potential bi-directional brain-lung interactions by examining posttraumatic lung infection at 3- or 60-days after injury. Animals subjected to TBI showed increased mortality after infection with Streptococcus pneumoniae Type 3 (Sp) at both 3 and 60 days post-injury. However, mortality was greater with infection at 60 days following TBI and exacerbated brain injury, with increased markers of neuroinflammation including TNF-α, IL-1β, and NADPH oxidase 2 (NOX2) in the injured cortex. In the lung, TBI followed by infection resulted increased bacterial burden and pathology. Analysis of Ly6C+ infiltrating monocytes in the lungs of mice infected with Sp 3 days post-injury demonstrated that these cells were less able to produce TNF-α, ROS, and IL-1β in response to infection. In contrast, lung-infiltrating Ly6C+ monocytes in mice subjected to infection 60 days post-TBI produced twice as much IL-1β and 50% more ROS as Ly6C+ monocytes from Sham-infected mice. These data show that TBI causes immune alterations, both acutely and chronically, that may contribute to susceptibility to infection.