Downregulated IRF8 in Monocytes and Macrophages of Patients with Systemic Sclerosis May Aggravate the Fibrotic Phenotype

Ototake, Yasushi; Yamaguchi, Yukie; Asami, Miho; Komitsu, Noriko; Akita, Asami; Watanabe, Tomoya; Kanaoka, Miwa; Kurotaki, Daisuke; Tamura, Tomohide; Aihara, Michiko

doi:10.1016/j.jid.2021.02.015

Cited by 30 publications

(19 citation statements)

References 35 publications

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“…As IRF8 has been reported as a critical positive regulator of IL-12 production (Holtschke et al, 1996; Masumi et al, 2002), a link between its downregulation and the reduced production of IL-12 observed in Cish −/− MØs seemed to offer a rationale for the functional impairment observed in these cells. Earlier studies provided circumstantial evidence to support the idea that the downregulation/silencing of IRF8 could represent a defining moment in favoring the development of M2-like MØs through the increased expression of M2 MØs genes (Ototake et al, 2021; Twum et al, 2019; Waight et al, 2013). Our data demonstrated that IRF8 bound in the vicinity of many genes that have been associated with MØ polarization, suggesting a critical instructive role in controlling M1 like features.…”

Section: Discussionmentioning

confidence: 99%

CIS calibrates GM-CSF signalling strength to regulate macrophage polarization via a STAT5-IRF8 axis

Zhang

Rautela

Bediaga

et al. 2022

Preprint

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The cytokine granulocyte-macrophage-colony stimulating factor (GM-CSF) possesses the ability to differentiate macrophages with opposing functions, namely proinflammatory M1-like and immunosuppressive M2-like. Despite the importance and opposing functional outcomes of these processes, the intrinsic mechanism that regulates the functional polarization of macrophages under GM-CSF signaling remains elusive. Here we show that GM-CSF induced macrophages polarisation resulted in the expression of the Cytokine-inducible SH2-containing protein (CIS), and that CIS deficiency diverted differentiation of monocytes into immunosuppressive M2-like macrophages expression. CIS deficiency resulted in the hyperactivation of the JAK-STAT5 signaling pathway, consequently promoting the downregulation of the transcription factor Interferon Regulatory Factor 8 (IRF8). Loss and gain of function approaches highlighted IRF8 as a critical instructor of the M1-like polarisation program. In vivo, CIS deficiency led to skewing to M2-like macrophages, which induced strong Th2 immune responses characterised by the development of severe experimental asthma. Collectively, we reveal a CIS-censored mechanism interpreting the opposing actions of GM-CSF in macrophages differentiation and uncovering its role in controlling allergic inflammation.

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Section: Discussionmentioning

confidence: 99%

CIS calibrates GM-CSF signalling strength to regulate macrophage polarization via a STAT5-IRF8 axis

Zhang

Rautela

Bediaga

et al. 2022

Preprint

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“…This transcription factor plays an important role in differentiation and regulation of monocytes and macrophages (49). Furthermore, variants in IRF8 have been associated with monocyte counts across different populations (50), and a downregulation of IRF8 in monocytes and macrophages of SSc patients that may affect the fibrotic phenotype of the disease was reported (51). A recent study demonstrated that the deletion of an enhancer region corresponding with our SSc GWAS locus in mice model decreased Irf8 expression, resulting in an overproduction of inflammatory Ly6c + monocytes (52).…”

Section: Discussionmentioning

confidence: 99%

Functional genomics in primary T cells and monocytes identifies mechanisms by which genetic susceptibility loci influence systemic sclerosis risk

González‐Serna

Shi

Kerick

et al. 2022

Preprint

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ObjectivesSystemic sclerosis (SSc) is a complex autoimmune disease with a strong genetic component. However, most of the causal genes and variants are still unknown. The challenge in the post-GWAS era is to use functional genomics to translate genetic findings into patients’ benefit, particularly in disease-relevant cell types.MethodsPromoter capture Hi-C (pCHi-C) and RNA sequencing experiments were performed in a total of 30 samples corresponding to CD4+ T cells and CD14+ monocytes (15 samples each) from SSc patients and healthy controls to link SSc-associated variants with their target genes, followed by differential expression and differential interaction analyses between both cell types. We also aimed to identify potential drugs that could be repurposed for its use in SSc.ResultsWe linked SSc-associated loci to 39 new potential target genes, confirming 7 previously assigned genes. We highlight novel causal genes, such as CXCR5 as the most probable candidate gene for the DDX6 locus. Some SSc confirmed genes such as IRF8, STAT4, or CD247 interestingly showed cell type specific interactions. We also identified 15 potential drug targets already in use in other similar immune-mediated diseases that could be repurposed for SSc treatment. Furthermore, we observed that interactions are directly related with the expression of important genes implicated in cell type specific pathways.ConclusionsOur study reveals potential causal genes for SSc-associated loci, some of them acting in a cell type specific manner, suggesting novel biological mechanisms that may mediate SSc pathogenesis.

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“…The de nition of functional phenotypes of macrophages during the pathogenesis of SSc remains controversial. There are reports that "M2" macrophages positive for CD206, CD163, and CD204 are activated and functionally pro brotic in SSc patients [10][11][12][13]. Upregulated IL-4 and IL-13 levels in serum were also demonstrated [14].…”

Section: Introductionmentioning

confidence: 94%

Neutrophil-driven CD206hiMHCIIlo macrophages are critical for skin fibrosis during systemic sclerosis

shi¹,

Gong

Ding

et al. 2022

Preprint

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Systemic sclerosis (SSc) is a recalcitrant autoimmune disease characterized by progressive fibrosis in the skin and internal organs, such as the lungs. A key feature of this disease is the infiltration of innate immune cells, yet, how they contribute to the pathogenesis of SSc is largely unknown. Here, we demonstrated that the CD206hiMHCIIlo macrophages were the dominant immune cell population accumulated in the fibrotic skin of SSc mice, and these cells were found to be critical in mediating the profibrotic response by producing TGF-β1 in a MerTK signaling-dependent manner. Interestingly, the neutrophil infiltration was a prerequisite for the accumulation of CD206hiMHCIIlo macrophages and depletion of neutrophils or inhibition of CXCR1/2 could reduce CD206hiMHCIIlo macrophages and alleviate SSc progression. Detailed investigations revealed that in the fibrotic skin, neutrophils released neutrophil extracellular traps (NETs) ensnared macrophages and were responsible for the differentiation of CD206hiMHCIIlo macrophages. Our findings uncovered a key role of the neutrophil-macrophage-fibrosis axis in the pathogenesis of SSc and provide critical information for the development of novel therapeutic strategies.

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Downregulated IRF8 in Monocytes and Macrophages of Patients with Systemic Sclerosis May Aggravate the Fibrotic Phenotype

Cited by 30 publications

References 35 publications

CIS calibrates GM-CSF signalling strength to regulate macrophage polarization via a STAT5-IRF8 axis

CIS calibrates GM-CSF signalling strength to regulate macrophage polarization via a STAT5-IRF8 axis

Functional genomics in primary T cells and monocytes identifies mechanisms by which genetic susceptibility loci influence systemic sclerosis risk

Neutrophil-driven CD206hiMHCIIlo macrophages are critical for skin fibrosis during systemic sclerosis

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