MyD88-dependent mechanisms of immune cell mobilization in response to bacterial infection

The mammalian host is confronted with a significant array of pathogenic bacteria, and thus must have available to it the mechanisms to limit the spread of, and ultimately defeat infections by these microbes. Upon infection, the presence of pathogenic microbes triggers the recruitment of immune cells primarily via activation of Toll-like receptors, which in turn signal via MyD88 to activate production of the pluripotent cytokines IL-1, TNF, and IFNgamma Given the multitude of bacterial types and routes of entry, inherent in the MyD88-dependent immune response is a requirement for sufficient diversity in the means of activating inflammation such that this wide variety of pathogens and routes is accounted for immunologically. As IL-1, TNF, and IFNgamma activate overlapping gene subsets and appear functionally similar based on prior studies of their roles in the inflammatory response, it is unknown whether these three cytokines are simply redundant or synergistic in their activity or whether they show functional specificity depending on the infection route or type of pathogenic bacterium encountered. To address this question, we examined the roles of IL-1, TNF, and IFNgamma in the mobilization of inflammatory cells in response to in vivo cutaneous Staphylococcus aureus and systemic Francisella tularensis infection using mice deficient in the receptors for IL-1, TNF, and IFNgamma to tease out specificities in the requirement for these cytokines to mobilize inflammatory cells. We found that MyD88-dependent IL-1 signaling was specifically required for recruitment of inflammatory cells to cutaneous S. aureus infection, whereas IFNgamma-dependent TNF production and not IL-1 was required to mobilize immune cells in response to F. tularensis. Taken together, these findings indicate that despite the seemingly redundant nature of these cytokines, they function nonredundantly in a pathogen- and route-specific fashion to mobilize inflammatory cells to the site of infection. These findings thus have significant implications scientifically in understanding the coevolution between the host immune system and pathogenic bacteria, and clinically in understanding how the mobilization of immune cells may be modulated in the context of infection and autoimmunity.