Increased M1 macrophage activity makes females more sensitive to Francisella tularensis infection

Abstract

Abstract The intensity of the inflammatory response differs between males and females, with females having a stronger basal inflammatory response compared with males. This leads to differences in sensitivity to autoimmune and infectious diseases. Males tend to be more susceptible to infectious diseases whereas females tend to be more susceptible to autoimmune diseases. However, certain infectious diseases cause disease by over stimulating an inflammatory response resulting in dysregulation of cytokine production and generation of a cytokine storm. We hypothesized that the elevated basal inflammatory state of females would make them more susceptible to inflammatory infectious diseases such as Francisella tularensis. Indeed, survival and immunological studies demonstrated that females had a stronger innate immune response and were more likely to succumb to tularemic-disease compared with males. Importantly, this dichotomy was independent of hormonal signaling. We traced the source of this elevated inflammatory response to alterations in the M1 and M2 macrophage activation profile. In females, M1 macrophages were activated earlier than in males in response to inoculation. These M1 macrophages from female mice showed a stronger activation both in vivo and in vitro cultures. This was consistent in both mouse and human systems. Our results demonstrate that females possess a higher abundance of M1 macrophages and that these M1 macrophages are more inflammatory in response to F. tularensis infection. This suggests that the consequence of the dichotomy between the male and female inflammatory response is dependent upon the mechanism of disease triggered by infectious diseases. Supported by grants from the NIH (SC1 GM122699-01A1) and NSF (MRI 1626587).