Anti-TNF treatment corrects IFN-?–dependent proinflammatory signatures in Blau syndrome patient–derived macrophages - 05/01/22
Abstract |
Background |
Blau syndrome (BS) is an autoinflammatory disease associated with mutations in nucleotide-binding oligomerization domain 2. Although treatments with anti-TNF agents have been reported to be effective, the underlying molecular mechanisms remain unclear.
Objective |
We aimed to elucidate the mechanisms of autoinflammation in patients with BS and to clarify how anti-TNF treatment controls the disease phenotype at the cellular level in clinical samples.
Methods |
Macrophages were differentiated from monocytes of 7 BS patients, and global transcriptional profiles of 5 patients were analyzed with or without IFN-γ stimulation. Macrophages were also generated from BS-specific induced pluripotent stem cells (iPSCs), and their transcriptome was examined for comparison.
Results |
Aberrant inflammatory responses were observed upon IFN-γ stimulation in macrophages from untreated BS patients, but not in those from patients treated with anti-TNF. iPSC-derived macrophages carrying a disease-associated mutation also showed IFN-γ–dependent accelerated inflammatory responses. Comparisons of peripheral blood– and iPSC-derived macrophages revealed the upregulation of nuclear factor kappa–light-chain enhancer of activated B cells (NF-κB) targets in unstimulated macrophages as a common feature.
Conclusions |
IFN-γ stimulation is one of the key signals driving aberrant inflammatory responses in BS-associated macrophages. However, long-term treatment with anti-TNF agents ameliorates such abnormalities even in the presence of IFN-γ stimulation. Our data thus suggest that preexposure to TNF or functionally similar cytokines inducing NF-κB–driven proinflammatory signaling during macrophage development is a prerequisite for accelerated inflammatory responses upon IFN-γ stimulation in BS.
Le texte complet de cet article est disponible en PDF.Key words : Blau syndrome, anti-TNF treatment, NF-κB, autoinflammatory loop, disease-specific iPS cells
Abbreviations used : BS, GO, iPSC, KEGG, MAPK, M-CSF, MDP, NF-κB, NOD2, PBMC, PCA, VEGFA, WT
Plan
| Funding was provided from the Core Center for iPS Cell Research of Research Center Network for Realization of Regenerative Medicine (JP21bm0104001) from the Japan Agency for Medical Research and Development (AMED; to M.K.S.), the Acceleration Program for Intractable Diseases Research Utilizing Disease-Specific iPS Cells from AMED (17935244 to M.K.S.), Practical Research Project for Rare/Intractable Diseases from AMED (17929899 to M.K.S.), Grants-in-Aid for Japanese Society for the Promotion of Science (JSPS) fellows (18J02122 to Y. Ki.), JSPS Grants-in-Aid for Scientific Research C (17K10243 to Y. Ka. and 19K08784 to N.K.), and a research grant from Ministry of Health, Labour and Welfare, Japan (to N.K.). |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
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| The first 2 authors contributed equally to this article, and both should be considered first author. |
Vol 149 - N° 1
P. 176 - janvier 2022 Retour au numéro
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