Objective: To investigate differentially expressed genes and related signaling pathways in patients with dermatomyositis/clinical amyopathic dermatomyositis (DM/CADM) complicated by interstitial lung disease or malignant tumors. Methods: From January 2017 to January 2018, 27 DM/CADM patients were enrolled from Department of Dermatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, and divided into 3 groups according to the complications: 10 with interstitial lung disease, 8 with malignant tumors, and 9 without interstitial lung disease or malignant tumors. Meanwhile, 7 healthy controls were enrolled into this study. High-throughput RNA sequencing was performed to screen differentially expressed genes in peripheral blood in the above 4 groups. Then, these genes were subjected to gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Results: Compared with the healthy controls, 4 820 up-regulated genes and 137 down-regulated genes were identified in DM/CADM patients; GO analysis revealed 49 significantly enriched items in the DM/CADM patients, 37 (75.5%) of which were associated with biological processes; KEGG analysis showed that differentially expressed genes were mainly enriched in infection-, tumor- and immune-related pathways in DM/CADM patients. Compared with the patients without interstitial lung disease or malignant tumors, 272 up-regulated genes and 158 down-regulated genes were identified in the patients with interstitial lung disease; GO analysis revealed 157 significantly enriched items, 114 (72.6%) of which were associated with biological processes; KEGG analysis showed that differentially expressed genes were mainly enriched in bacterial infection- and autoimmune/inflammatory-related pathways in the patients with interstitial lung disease. Compared with the patients without interstitial lung disease or malignant tumors, 398 up-regulated genes and 68 down-regulated genes were identified in the patients with malignant tumors; GO analysis revealed 117 significantly enriched items, 94 (80.3%) of which were associated with biological processes; KEGG analysis showed that differentially expressed genes were mainly enriched in glycosylation-, metabolism- and tumor-related signaling pathways in the patients with malignant tumors. Conclusions Differences existed in transcriptomes and pathways between the DM/CADM patients and healthy controls, as well as between the patients with interstitial lung disease or malignant tumors and patients without these complications. Bacterial infection- and cytokine/chemokine-related pathways were significantly enriched in the patients with DM/CADM complicated by interstitial lung disease, while those pathways related to glycosylation, protein metabolism, angtigen presentation and cytotoxic effects of natural killer cells were significantly enriched in the patients with DM/CADM complicated by malignant tumors.

High mobility group box 1 (HMGB1) has been reported to play an important role in experimental autoimmune encephalomyelitis (EAE). Astrocytes are important components of neurovascular units and tightly appose the endothelial cells of microvessels by their perivascular endfeet and directly regulate the functions of the blood-brain barrier. Astrocytes express more HMGB1 during EAE while the exact roles of astrocytic HMGB1 in EAE have not been well elucidated. Here, using conditional-knockout mice, we found that astrocytic HMGB1 depletion decreased morbidity, delayed the onset time, and reduced the disease score and demyelination of EAE. Meanwhile, there were fewer immune cells, especially pathogenic T cells infiltration in the central nervous system of astrocytic HMGB1 conditional-knockout EAE mice, accompanied by up-regulated expression of the tight-junction protein Claudin5 and down-regulated expression of the cell adhesion molecules ICAM1 and VCAM1 in vivo. In vitro, HMGB1 released from astrocytes decreased Claudin5 while increased ICAM1 and VCAM1 expressed by brain microvascular endothelial cells (BMECs) through TLR4 or RAGE. Taken together, our results demonstrate that HMGB1 derived from astrocytes aggravates EAE by directly influencing the immune cell infiltration-associated functions of BMECs.
Mice ; Animals ; Encephalomyelitis, Autoimmune, Experimental/metabolism* ; Astrocytes/metabolism* ; HMGB1 Protein/metabolism* ; Endothelial Cells/metabolism* ; Mice, Inbred C57BL ; Mice, Knockout ; Blood-Brain Barrier/metabolism*