SUMMARY
Alveolar macrophages (AMs) process lipid-rich pulmonary surfactant and have steady-state immunosuppressive
functions that support lung homeostasis. During infection, AMs can rapidly shift from anti-inflammatory to pro-
inflammatory programs to support pathogen clearance. Dysregulation in the balance of AM anti- and pro-
inflammatory responses leads to increased mortality in bacterial pneumonia. While it is well appreciated that the
lung microenvironment shapes tissue-specific AM function, very little is known about the persistent signaling
events that program AMs in health and disease, which limits our ability to manipulate AMs therapeutically. We
show that Cish, a negative regulator in the SOCS family, is constitutively expressed in AMs. Cish deficient AMs
have a lipid-laden foamy phenotype, increased GATA2 activity, and impaired inflammatory responses to
microbial stimuli. This proposal is centered around defining signaling mechanisms that link lung-specific stimuli
to macrophage function, with a focus on understanding the role of the CISH-GATA2 regulatory node in AM
programming, lung homeostasis, and bacterial pneumonia. Our central hypothesis is that lung cytokines
drive GATA2 activity to promote AM lipid metabolism and anti-inflammatory function, and that CISH
inhibits these processes to support functional plasticity in response to infection. In Aim 1, we will
determine mechanisms by which specific steady-state cytokines and associated kinases program AM
metabolism and inflammatory responsiveness. In Aim 2, we will define the role of the CISH-GATA2 regulatory
node in control of AM pro- and anti-inflammatory function during bacterial lung infection and resolution. This work
is significant because it will provide mechanistic insight into signaling processes that underlie AM programming,
a clearly important aspect of lung homeostasis and morbidity associated with pulmonary infection.
