The Rothchild laboratory focuses on the innate immune responses in the lung, studying how alveolar macrophages regulate inflammation at the airway-tissue interface. Positioned at the pulmonary mucosal barrier, alveolar macrophages are often the first cells to take up inhaled pathogens, performing a critical function as immune sentinels of the lung. In this role, alveolar macrophages must rapidly sense foreign pathogens and alert other immune cells to assist in host defense. In addition, alveolar macrophages must perform an essential homeostatic role clearing debris and dead cells from the airway without triggering excessive inflammation, yet it is unknown how alveolar macrophages balance these two seemingly opposing functions.

We study the role of alveolar macrophages during 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.

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 and antagonists, 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, delaying subsequent immune events, and leading to impaired bacterial control. We also aim to understand how regulation of pulmonary inflammation by Nrf2 might be applicable to other respiratory infections and inflammatory conditions.

Other projects in the laboratory are focused on understanding how alveolar macrophages integrate signals from airborne particulates and systemic inflammation and characterizing the regulatory pathways that assist alveolar macrophages in maintaining pulmonary homeostasis, allowing for sufficient immune responses to infection while preventing unnecessary pathology and lung damage. While our work focuses on this balance during Mtb infection, these pathways and regulatory networks likely play a role in maintaining pulmonary homeostasis during other respiratory infections, including SARS-CoV-2, as well as in non-communicable inflammatory conditions such as COPD and asthma.