Integrative single-cell analysis of cardiac and pulmonary sarcoidosis using publicly available cardiac and bronchoalveolar lavage fluid sequencing datasets

Abstract

IntroductionCardiac presentation of autoimmune sarcoidosis, known as cardiac sarcoidosis (CS), is a poorly understood disease with high mortality and low diagnosis rate. While CS is an immunological syndrome, little is known about how cardiac parenchymal and stromal cells mediate its pathogenesis. Moreover, while most current sarcoidosis research is based on research in pulmonary sarcoidosis (PS), it remains unclear how much both presentations of sarcoidosis overlap. To tackle these concerns, we leveraged publicly available sarcoidosis transcriptomic datasets.MethodsTwo publicly available bronchoalveolar lavage single-cell RNA sequencing datasets were integrated to analyze PS relative to control. Additionally, two publicly available cardiac single-nucleus RNA sequencing datasets were integrated to analyze CS relative to control. Following integration, we ran cell-cell communication, transcription factor, and differential expression analyses on parenchymal, stromal, and immune subsets identified in our analysis.ResultsOur analysis revealed that there was an expansion of stromal and immune cells in PS and CS. We also observed upregulation of Th17.1 and attenuated activation transcriptional profiles in the immune cells of CS and PS relative to control. Additionally, we found upregulation of pro-inflammatory and pro-fibrotic transcriptional profiles in the cardiac stromal cells of CS relative to control. We also found that cardiomyocytes exhibited upregulated cardiac stress and proliferation transcriptional profiles in CS relative to control.ConclusionsOur integrative transcriptomic analysis shows that despite tissue-specific differences, there are shared transcriptional trends between CS and PS. It also shows that stromal and parenchymal populations exhibit transcriptional trends that could explain their pathogenic role in CS.

Autoimmune Myocarditis, Old Dogs and New Tricks

“…Although the specific antigen is unidentified, studies indicate the involvement of T cells, particularly IFN-γ-producing Th17 cells, as a key immunologic feature in sarcoidosis. 216,217 Recent research utilizing single-cell or single-nuclei RNA sequencing revealed that distinct macrophage subsets from different origins contribute to sarcoidotic granuloma formation in the heart, with upregulated mTOR (mammalian target of rapamycin) signaling and alternative activation pathway as well as downregulated cytokine signaling and phagocytosis functions. 194,217 These studies further demonstrated a dysregulated transcription program in nonhematopoietic resident heart cells under conditions of cardiac sarcoidosis including profibrotic, proinflammatory fibroblasts; fibroblast-like, angiogenic endothelial cells; and proinflammatory, stressrelated cardiomyocytes.…”

“…216,217 Recent research utilizing single-cell or single-nuclei RNA sequencing revealed that distinct macrophage subsets from different origins contribute to sarcoidotic granuloma formation in the heart, with upregulated mTOR (mammalian target of rapamycin) signaling and alternative activation pathway as well as downregulated cytokine signaling and phagocytosis functions. 194,217 These studies further demonstrated a dysregulated transcription program in nonhematopoietic resident heart cells under conditions of cardiac sarcoidosis including profibrotic, proinflammatory fibroblasts; fibroblast-like, angiogenic endothelial cells; and proinflammatory, stressrelated cardiomyocytes. These findings are further supported by an animal study showing that the activation of mTOR signaling specifically in CD11c-expressing cells in mice resulted in a granulomatous phenotype and fibrosis in the heart, resembling cardiac sarcoidosis in humans, suggesting mTOR signaling as a potential therapeutic target (Table ).…”