CISH attenuates homeostatic cytokine signaling to promote lung-specific macrophage programming and function.

Tissue-specific cytokine stimuli orchestrate specialized homeostatic functions of resident macrophages. In the lung, steady-state signaling by the cytokine GM-CSF is critical for alveolar macrophage (AM) development and function. Here, we showed that CISH, a suppressor of cytokine signaling (SOCS) family member that is acutely induced by diverse cytokine stimuli in many tissues, was expressed constitutively in AMs in response to steady-state GM-CSF signaling. deficiency led to the generation of foamy AMs and the accumulation of pulmonary surfactant. These phenotypic changes were associated with enhanced activation of STAT5, AKT, and ERK and increased expression of the gene encoding the transcription factor GATA2. RNA-seq analysis of AMs revealed a set of dysregulated immune and lipid-process modules, including the increased expression of genes enriched for GATA2-binding motifs. Last, -deficient, bone marrow–derived macrophages showed increased expression and accumulated more lipid upon incubation with bronchoalveolar lavage fluid compared with -sufficient cells. Thus, CISH is part of a feedback loop that constrains homeostatic cytokine signaling and expression to maintain AM identity and function.