THE PROBLEM
Macrophages are immune cells that respond rapidly to infection and tissue injury. They also have important roles in maintaining normal tissue structure and function. Improper macrophage function has been implicated in pathologies relevant to the DoD’s mission and to public health overall, including cancer, Alzheimer’s disease, traumatic brain injury and chronic wounds. This laboratory attempts to understand how macrophages sense and respond to their environment, and whether these normal sensing mechanisms are disrupted or heightened in pathological settings like those mentioned above.
OUR APPROACH
The lab accomplishes these aims by utilizing two bedrock approaches: a cell culture-based microfluidic gradient system to mechanistically dissect macrophage guidance pathways, and intravital multiphoton microscopy to directly observe macrophage activation and localization in live mice. These approaches combined to reveal that the actin-polymerizing Arp2/3 complex is required for macrophage haptotaxis, but not chemotaxis, and that endogenous monocytes lacking Arp2/3 function migrated rapidly and directionally in response to ear wounding in vivo (Rotty et al., Developmental Cell, 2017).
My lab’s initial emphasis is on haptotaxis - a directional guidance system that confers to cells the ability to sense immobilized surface cues, like extracellular matrix. This guidance system is not well defined beyond Arp2/3, and its in vivo function remains unclear. Ongoing projects include:
- Determining whether an Arp2/3-activating co-incidence circuit governs haptotaxis
- Identifying how Arp2/3 regulates macrophage inflammatory activation
- Defining the in vivo function of haptotaxis – Is it immunomodulatory?