Abstract Due to widespread use of immune suppressive therapies, the incidence of life-threatening lung infections with fungal pathogens is increasing. Although protective immunity against Aspergillus fumigatus (Af) and other fungal pathogens is critical for host survival, excessive inflammation can also inhibit disease resolution. The potential to therapeutically target anti-inflammatory pathways to facilitate the resolution of fungal infection and associated pathology is understudied, primarily due to the difficulties of dissociating immune pathology from the pathologies directly linked to invasive fungal growth. We recently observed an increase in mortality, immune pathology, and antifungal inflammatory cytokine production in mice that lack the insulin-regulating cytokine adiponectin, thus establishing a novel link between the known anti-inflammatory role for adiponectin and control of excessive inflammation in fungal infection. Although most studies have focused on the role of adipose-derived adiponectin, our data suggest that adiponectin levels are regulated locally in the lung during IA. The role of non-adipose-tissue-derived adiponectin in controlling fungal infection- induced inflammation is unknown. Similarly, it is unclear whether macrophages and other immune cells are directly responsive to the immune-regulatory actions of adiponectin during IA. Using an unbiased, systems biology approach to study the impact of adiponectin during IA, we identified tristetraprolin (TTP) as a potential regulator. TTP is an RNA-binding and degrading protein known to regulate the production of multiple cytokines. Importantly, we have developed an experimental approach that allows us to separate immunopathology from fungal growth. With this approach we can specifically interrogate the mechanisms by which adiponectin regulates excessive pulmonary inflammation. Based on our results, our central hypothesis is that locally produced adiponectin acts directly on macrophages via AdipoR1/R2 engagement to activate TTP and subsequent cytokine degradation. In AIM 1, we will determine if adiponectin produced in non-adipose tissues such as the lungs is critical for protection from IA. In AIM 2, we will determine if adiponectin protects against inflammatory pathology in IA via AdipoR1/R2 on macrophages. We anticipate that these studies will delineate mechanisms of adiponectin-mediated inhibition of lung immune pathology. Our proposed work will identify novel targets with therapeutic potential and open new avenues of research in the development of detrimental immunity to infection.