Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis

Sreih, Antoine; Ezzedine, Rana; Leng, Lin; Fan, Juan; Yao, Jie; Reid, Duncan; Piecychna, Marta; Carette, Simon; Cuthbertson, David; Dellaripa, Paul F.; Hoffman, Gary S.; Khalidi, Nader; Koening, Curry L.; Langford, Carol A.; Mahr, Alfred; McAlear, Carol A.; Maksimowicz-McKinnon, Kathleen; Monach, Paul A.; Seo, Philip; Specks, Ulrich; Clair, E. William St.; Stone, John H.; Ytterberg, Steven R.; Edberg, Jeffrey C.; Merkel, Peter A.; Bucala, Richard

doi:10.1002/art.40655

Cited by 12 publications

(12 citation statements)

References 46 publications

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“…32). The latter mice mimic the approximate 2-fold increase in Mif transcription observed in high MIF expressor genotypes (32). At all DPIs, Mif -/samples contained no measurable MIF, as expected, and Mif-lung-tg BAL contained at least 2-fold more MIF relative to Mif +/+ BAL ( Figure 1A).…”

Section: Iav Infection Promotes Mif Protein Release Into the Airspacesupporting

confidence: 72%

“…All animals used for the study were male mice between 2 and 4 months of age and of pure C57BL/6 background. Mif -/and Mif-lung-tg (32,45) mice that were both on a pure C57BL/6 background were used for the study. The Mif-lung-tg mice overexpress Mif in alveolar type II epithelial cells; specifically, these mice had a 0.4-Kb DNA fragment with mouse Mif cDNA inserted into the expression plasmid under control of a CC10 promoter as previously reported (46).…”

Section: Mice and Cell Culturesmentioning

confidence: 99%

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Macrophage migration inhibitory factor enhances influenza-associated mortality in mice

Smith¹,

Tyrell²,

Kulkarni³

et al. 2019

JCI Insight

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Section: Iav Infection Promotes Mif Protein Release Into the Airspacesupporting

confidence: 72%

Section: Mice and Cell Culturesmentioning

confidence: 99%

Macrophage migration inhibitory factor enhances influenza-associated mortality in mice

Smith¹,

Tyrell²,

Kulkarni³

et al. 2019

JCI Insight

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“…Gene expression studies indicate that a microsatellite within the MIF promoter (−794 CATT 5-8 , rs5844572) influences MIF expression such that the CATT 5 repeat is a lowexpression allele and the CATT 6 , CATT 7 , and CATT 8 repeats are progressively higher-expression alleles (5,6). Higher CATT repeat number within the MIF promoter also has been linked genetically to susceptibility to or clinical severity of numerous autoimmune inflammatory and infectious disorders (5)(6)(7)(8)(9)(10). The transcription factor inverted CCAAT box-binding protein 90 kd (ICBP90) (also referred to as UHRF1) binds to the MIF promoter microsatellite and is essential for −794 CATT 5-8 length-dependent regulation of MIF transcription (11).…”

Section: Introductionmentioning

confidence: 99%

ICBP90 Regulates MIF Expression, Glucocorticoid Sensitivity, and Apoptosis at the MIF Immune Susceptibility Locus

Yao

Leng

et al. 2021

Arthritis & Rheumatology

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Objective Macrophage migration inhibitory factor (MIF) is an inflammatory and neurorendocrine mediator that counterregulates glucocorticoid immunosuppression. MIF polymorphisms, which comprise a variant promoter microsatellite (−794 CATT5–8), are linked genetically to autoimmune disease severity and to glucocorticoid resistance. While invasive stimuli increase MIF expression, MIF also is up‐regulated by glucocorticoids, which serve as a physiologic regulator of inflammatory responses. This study was undertaken to define interactions between the MIF promoter, the glucocorticoid receptor (GR), and the transcription factor inverted CCAAT box binding protein 90 kd (ICBP90) (also referred to as UHRF1), which binds to the promoter in a −794 CATT5–8 length–dependent manner, to regulate MIF transcription. Methods Interactions of ICBP90, GR, and activator protein 1 (AP‐1) with MIF −794 CATT5–8 promoter constructs were assessed by coimmunoprecipitation, Western blotting, and genetic knockdown. Nuclear colocalization studies were performed using anti–transcription factor antibodies and confocal microscopy of glucocorticoid‐treated cells. MIF transcription was studied in CEM‐C7 T cells, and the impact of the MIF −794 CATT5–8 microsatellite variation confirmed in peripheral blood T cells and in rheumatoid synovial fibroblasts of defined MIF genotype. Functional interactions were quantified by apoptosis and apoptotic signaling in high‐ and low‐genotypic MIF–expressing human cells. Results We defined functional interactions between the transcription factors ICBP90, the GR, and AP‐1 that up‐regulated MIF transcription in a −794 CATT5–8 length–dependent manner. Experimental reduction of ICBP90, GR, or AP‐1 decreased MIF expression and increased glucocorticoid sensitivity, leading to enhanced apoptosis in T lymphocytes and in rheumatoid synovial fibroblasts. Conclusion These findings suggest a mechanism for genetic variation of glucocorticoid‐regulated MIF transcription, with implications for autoimmune disease severity and glucocorticoid responsiveness.

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“…Of note, neutrophils from healthy donors secrete preformed macrophage migration inhibitory factor (MIF) during secondary necrosis, and it is speculated that MIF acts as a danger signal for insufficient clearance of apoptotic neutrophils [ 116 , 117 ]. Interestingly, abnormalities of the MIF gene are more frequent among GPA patients, and using a mouse model, it was demonstrated that overexpression of MIF promotes lung granulomas and increased mortality, thus supporting a role for MIF in GPA [ 118 ]. Apart from neutrophils and monocytes, NG2 + pericytes present around capillaries and arterioles also express MIF [ 31 ].…”

Section: Cells Molecules and Mechanisms Of The Innate Immune Response Fuel The Granulomatous Inflammation In Gpamentioning

confidence: 99%

Granulomatous Inflammation in ANCA-Associated Vasculitis

Müller

Krause

Kerstein-Stähle

et al. 2021

IJMS

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ANCA-associated vasculitis (AAV) comprises granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). While systemic vasculitis is a hallmark of all AAV, GPA is characterized by extravascular granulomatous inflammation, preferentially affecting the respiratory tract. The mechanisms underlying the emergence of neutrophilic microabscesses; the appearance of multinucleated giant cells; and subsequent granuloma formation, finally leading to scarred or destroyed tissue in GPA, are still incompletely understood. This review summarizes findings describing the presence and function of molecules and cells contributing to granulomatous inflammation in the respiratory tract and to renal inflammation observed in GPA. In addition, factors affecting or promoting the development of granulomatous inflammation such as microbial infections, the nasal microbiome, and the release of damage-associated molecular patterns (DAMP) are discussed. Further, on the basis of numerous results, we argue that, in situ, various ways of exposure linked with a high number of infiltrating proteinase 3 (PR3)- and myeloperoxidase (MPO)-expressing leukocytes lower the threshold for the presentation of an altered PR3 and possibly also of MPO, provoking the local development of ANCA autoimmune responses, aided by the formation of ectopic lymphoid structures. Although extravascular granulomatous inflammation is unique to GPA, similar molecular and cellular patterns can be found in both the respiratory tract and kidney tissue of GPA and MPA patients; for example, the antimicrobial peptide LL37, CD163+ macrophages, or regulatory T cells. Therefore, we postulate that granulomatous inflammation in GPA or PR3-AAV is intertwined with autoimmune and destructive mechanisms also seen at other sites.

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Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis

Cited by 12 publications

References 46 publications

Macrophage migration inhibitory factor enhances influenza-associated mortality in mice

Macrophage migration inhibitory factor enhances influenza-associated mortality in mice

ICBP90 Regulates MIF Expression, Glucocorticoid Sensitivity, and Apoptosis at the MIF Immune Susceptibility Locus

Granulomatous Inflammation in ANCA-Associated Vasculitis

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