Photo credit: Pamelia Lim
Human lungs inhale ~8,000 liters of air daily, leaving lungs highly vulnerable to airborne exposures. Alveolar macrophages (AM) are airway-resident innate cells that phagocytose debris, dead cells, surfactant, and foreign material. AMs serve a critical role maintaining homeostatic airway clearance and sensing inhaled pathogens, but their function during Mycobacterium tuberculosis (Mtb) infection is not well understood. The focus of our research group is to study the role of AMs as innate immune sentinels and regulators of inflammation during Mtb infection. Mycobacterium tuberculosis (Mtb) infection, a respiratory pathogen that kills almost 1.5 million people each year and is the leading cause of infection-related death worldwide. Alveolar macrophages play a unique role during Mtb infection, because they are the very first cell to become infected after aerosol transmission and remain the dominant cell type infected through the first 10 days. Therefore, the speed and quality of the response of these macrophages influence disease outcome.
Role of myeloid NRF2 expression during Mtb infection
Our previous work found that alveolar macrophages initially respond to Mtb in a non-inflammatory manner, which is dependent on expression of the transcription factor NRF2. NRF2 is a master regulator for an antioxidant/oxidative stress response that regulates pathways such as glutathione metabolism and antioxidant production. Mtb-infected cells must eventually initiate innate cell recruitment and priming of the adaptive response, and the molecular basis for these events remains poorly understood. Using NRF2 conditional knock-out strains and NRF2 chemical agonists , we aim to characterize how the early induction of a cell protective program by NRF2 prevents alveolar macrophages from mounting a pro-inflammatory response to Mtb infection. We recently identified a role for NRF2 in limiting alveolar macrophage antigen presentation and their ability to activate CD4+ T cells. We are now focused on other roles for NRF2 including regulation of cell death, delay of immune events, and impacts on pulmonary inflammation and lipid metabolism.
Alveolar macrophages are innate sensors and inflammatory mediators
We are interested in understanding how alveolar macrophages maintain dual functions within the pulmonary airway: 1) as innate sensors, recognizing Pathogen Associated Molecular Patterns (PAMPs) from direct infection, 2) as inflammatory mediators, responding to inflammatory signals in the environment derived from other responding cells. We aim study AM innate sensing pathways and the molecular mechanisms that limit detection and response to pathogens.
Photo credit: Greg Olson/Alissa Rothchild
Remodeling of alveolar macrophages by vaccination and prior infection
We are interested in the signals that remodel alveolar macrophages during prior infection/exposure and by vaccination. We have found that different inflammatory environments alter the response of alveolar macrophages. Using BCG vaccination and contained Mtb infection, we demonstrated that alveolar macrophage responses to Mtb show plasticity and cell-intrinsic and durable changes. Which inflammatory signals are responsible for alveolar macrophage remodeling? What are the consequences for the host response?
In addition to murine models, we also profile human alveolar macrophages as part of the Cascade IMPAc-TB (Immune Mechanisms of Protection Against Mycobacterium tuberculosis) consortium, to examine effective host immune responses in small animal models and human cohorts.
Rothchild Lab 