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- Title
CISH attenuates homeostatic cytokine signaling to promote lung-specific macrophage programming and function.
- Authors
Shoger, Karsen E.; Cheemalavagu, Neha; Cao, Yuqi M.; Michalides, Brandon A.; Chaudhri, Virendra K.; Cohen, Jonathan A.; Singh, Harinder; Gottschalk, Rachel A.
- Abstract
Calibrating macrophages for lung homeostasis: Dysregulation of alveolar macrophages (AMs) in the lung results in the accumulation of surfactant, pulmonary alveolar proteinosis, and respiratory failure if left untreated. Shoger et al. found that CISH, a member of the suppressor of cytokine signaling (SOCS) family, was increased in abundance in response to the homeostatic cytokine GM-CSF. Loss of CISH led to increased GM-CSF signaling, the generation of enlarged, foamy AMs, the increased abundance and activity of the transcriptional regulator GATA2, and dysregulation of genes responsible for AM function. These findings suggest that the fine-tuning of cytokine signaling is required to regulate tissue-specific pathways that maintain macrophage identity 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. Cish 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 Cish−/− AMs revealed a set of dysregulated immune and lipid-process modules, including the increased expression of genes enriched for GATA2-binding motifs. Last, Cish-deficient, bone marrow–derived macrophages showed increased Gata2 expression and accumulated more lipid upon incubation with bronchoalveolar lavage fluid compared with Cish-sufficient cells. Thus, CISH is part of a feedback loop that constrains homeostatic cytokine signaling and Gata2 expression to maintain AM identity and function.
- Subjects
CYTOKINES; SUPPRESSORS of cytokine signaling; PULMONARY alveolar proteinosis; ALVEOLAR macrophages; MACROPHAGES; LUNGS
- Publication
Science Signaling, 2021, Vol 14, Issue 698, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.abe5137