T-cell–restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung

Iriguchi, Shoichi; Kikuchi, Norihiro; Kaneko, Shin; Noguchi, Emiko; Morishima, Yuko; Matsuyama, Masashi; Yoh, Keigyou; Takahashi, Satoru; Nakauchi, Hiromitsu; Ishii, Yukio

doi:10.1182/blood-2014-05-575225

Cited by 22 publications

(17 citation statements)

References 63 publications

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“…It has recently been reported that hyperactivation of Th1 cells causes PAP. In this model, the expression of Bach2 is increased in AMs (36). This observation is consistent with a role of Bach2 in restricting responses to inflammation.…”

Section: Alveolar Macrophage Identity Crisis In Bach2-deficient Micesupporting

confidence: 89%

Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis

Ebina-Shibuya

Matsumoto

Kuwahara

et al. 2017

Journal of Biological Chemistry

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Pulmonary alveolar proteinosis (PAP) is a severe respiratory disease characterized by dyspnea caused by accumulation of surfactant protein. Dysfunction of alveolar macrophages (AMs), which regulate the homeostasis of surfactant protein, leads to the development of PAP; for example, in mice lacking BTB and CNC homology 2 (Bach2). However, how Bach2 helps prevent PAP is unknown, and the cell-specific effects of Bach2 are undefined. Using mice lacking in specific cell types, we found that the PAP phenotype of-deficient mice is due to deficiency in more than two types of immune cells. Depletion of hyperactivated T cells in-deficient mice restored normal function of AMs and ameliorated PAP. We also found that, in -deficient mice, hyperactivated T cells induced gene expression patterns that are specific to other tissue-resident macrophages and dendritic cells. Moreover,-deficient AMs exhibited a reduction in cell cycle progression. IFN-γ released from T cells induced Bach2 expression in AMs, in which Bach2 then bound to regulatory regions of inflammation-associated genes in myeloid cells. Of note, in AMs, Bach2 restricted aberrant responses to excessive T cell-induced inflammation, whereas, in T cells, Bach2 puts a brake on T cell activation. Moreover, Bach2 stimulated the expression of multiple histone genes in AMs, suggesting a role of Bach2 in proper histone expression. We conclude that Bach2 is critical for the maintenance of AM identity and self-renewal in inflammatory environments. Treatments targeting T cells may offer new therapeutic strategies for managing secondary PAP.

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Section: Alveolar Macrophage Identity Crisis In Bach2-deficient Micesupporting

confidence: 89%

Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis

Ebina-Shibuya

Matsumoto

Kuwahara

et al. 2017

Journal of Biological Chemistry

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“…However, these observations suggest overlapping pathophysiologic pathways between MAS and SJIA‐LD, in which the inflammatory cytokine milieu that drives MAS also promotes alveolar macrophage dysfunction (Figure ). Consistent with this hypothesis, mice with T cell–restricted overexpression of T‐bet driving IFNγ production demonstrated both dysfunction of bone marrow macrophages, resulting in erythrophagocytosis, and dysfunction of alveolar macrophages with development of PAP‐like lung pathology ().…”

Section: Discussionmentioning

confidence: 78%

Systemic Juvenile Idiopathic Arthritis–Associated Lung Disease: Characterization and Risk Factors

Schulert

Yasin

Carey

et al. 2019

Arthritis & Rheumatology

160

251

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Objective Systemic juvenile idiopathic arthritis (JIA) is associated with a recently recognized, albeit poorly defined and characterized, lung disease (LD). The objective of this study was to describe the clinical characteristics, risk factors, and histopathologic and immunologic features of this novel inflammatory LD associated with systemic JIA (designated SJIA‐LD). Methods Clinical data collected since 2010 were abstracted from the medical records of patients with systemic JIA from the Cincinnati Children's Hospital Medical Center. Epidemiologic, cellular, biochemical, genomic, and transcriptional profiling analyses were performed. Results Eighteen patients with SJIA‐LD were identified. Radiographic findings included diffuse ground‐glass opacities, subpleural reticulation, interlobular septal thickening, and lymphadenopathy. Pathologic findings included patchy, but extensive, lymphoplasmacytic infiltrates and mixed features of pulmonary alveolar proteinosis (PAP) and endogenous lipoid pneumonia. Compared to systemic JIA patients without LD, those with SJIA‐LD were younger at the diagnosis of systemic JIA (odds ratio [OR] 6.5, P = 0.007), more often had prior episodes of macrophage activation syndrome (MAS) (OR 14.5, P < 0.001), had a greater frequency of adverse reactions to biologic therapy (OR 13.6, P < 0.001), and had higher serum levels of interleukin‐18 (IL‐18) (median 27,612 pg/ml versus 5,413 pg/ml; P = 0.047). Patients with SJIA‐LD lacked genetic, serologic, or functional evidence of granulocyte–macrophage colony‐stimulating factor pathway dysfunction, a feature that is typical of familial or autoimmune PAP. Moreover, bronchoalveolar lavage (BAL) fluid from patients with SJIA‐LD rarely demonstrated proteinaceous material and had less lipid‐laden macrophages than that seen in patients with primary PAP (mean 10.5% in patients with SJIA‐LD versus 66.1% in patients with primary PAP; P < 0.001). BAL fluid from patients with SJIA‐LD contained elevated levels of IL‐18 and the interferon‐γ–induced chemokines CXCL9 and CXCL10. Transcriptional profiling of the lung tissue from patients with SJIA‐LD identified up‐regulated type II interferon and T cell activation networks. This signature was also present in SJIA‐LD human lung tissue sections that lacked substantial histopathologic findings, suggesting that this activation signature may precede and drive the lung pathology in SJIA‐LD. Conclusion Pulmonary disease is increasingly detected in children with systemic JIA, particularly in association with MAS. This entity has distinct clinical and immunologic features and represents an uncharacterized inflammatory LD.

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“…The results identified a novel mechanism by which increased expression of T-bet, exclusively in T lymphocytes, spontaneously drives the pathogenesis of both MDS and secondary PAP in a dose-dependent manner. [ 20 ] In this report, 1 case developed secondary PAP happened at the same time as MDS, and the other occurs after MDS. We speculate that the functional impairment of mononuclear phagocytes in the lung associated with aberrant hematopoiesis of myeloid cells might account for the development of secondary PAP in our patients.…”

Section: Discussionmentioning

confidence: 71%

Clinical features of secondary pulmonary alveolar proteinosis associated with myelodysplastic syndrome

Liu

Chen²,

Qiu³

et al. 2017

Medicine

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Rationale:Pulmonary alveolar proteinosis (PAP) is a rare lung disorder characterized by the abnormal accumulation of alveolar surfactant protein in alveolar spaces. Secondary PAP can result from myelodysplastic syndrome (MDS).Patient concerns:But most reports described a single case; here we reported 2 cases of PAP secondary to MDS. One case developed secondary PAP at the same time as MDS, and the other developed during the course of MDS.Diagnoses:The diagnosis of PAP was made by bronchoalveolar lavage and based on the identification of periodic acid-Schiff-positive proteinaceous material. Chest high resolution CT (HRCT) scans showed variable distribution of ground glass opacities, but crazy-paving appearance was not seen in our 2 cases.Interventions:Because the patients’ general conditions were poor, whole lung lavage was not used in the 2 cases.Outcomes:And the 2 cases’ prognoses were poor.Lessons:In conclusion, pulmonary physicians should suspect the possibility of secondary PAP when they encounter unexplained pulmonary infiltrates with some hematologic or infectious disease that shows diffuse bilateral GGO on an HRCT scan.

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T-cell–restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung

Cited by 22 publications

References 63 publications

Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis

Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis

Systemic Juvenile Idiopathic Arthritis–Associated Lung Disease: Characterization and Risk Factors

Clinical features of secondary pulmonary alveolar proteinosis associated with myelodysplastic syndrome

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