Interstitial macrophages (IMs) are a subpopulation of tissue resident macrophages (TRMs) present across all tissues, ranging from brain borders to kidneys. Across the different tissues they inhabit, IMs are subdivided into two subsets according to whether they express pro-inflammatory or reparative genes. This pattern of conservation further extends to their sub-anatomical localization, with one subset showing preferential association with blood vessels, whereas the other spatially maps to nerve bundles. Despite conserved cross-tissue gene expression patterns and localizations, to date only tissue-specific functions have been attributed to IMs, such as regulating peristalsis in the gut or the flow of cerebrospinal fluid in the brain. While zooming in on the lung, in this proposal, we aim to understand the cross-tissue niches that determine IM subset function, and how their dysfunction may lead to disease. These insights are important as TRMs are known to modulate highly debilitating inflammatory conditions such as Alzheimer's or Covid19 disease. Besides increasing our fundamental understanding of lung IMs, our results will also allow investigation of IMs across multiple tissues.