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Article ; Online: Fibroblast heterogeneity in pulmonary fibrosis: a new target for therapeutics development?

Tsoyi, Konstantin / Rosas, Ivan O

2024 Volume 63, Issue 2

MeSH term(s)	Humans ; Pulmonary Fibrosis/pathology ; Myofibroblasts ; Lung/pathology ; Fibroblasts/pathology
Language	English
Publishing date	2024-02-08
Publishing country	England
Document type	Editorial ; Comment
ZDB-ID	639359-7
ISSN	1399-3003 ; 0903-1936
ISSN (online)	1399-3003
ISSN	0903-1936
DOI	10.1183/13993003.02188-2023
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Zs.A 2322: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 292: Show issues

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Article ; Online: Targeting Danger Signals to Rescue Fibrosis.

Tsoyi, Konstantin / Rosas, Ivan O

American journal of respiratory cell and molecular biology

2022 Volume 66, Issue 5, Page(s) 468–470

MeSH term(s)	Humans ; Lung/pathology ; Lung Injury/pathology ; Pulmonary Fibrosis/pathology ; Radiation Injuries/pathology
Language	English
Publishing date	2022-03-09
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2022-0022ED
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Zs.A 2851: Show issues

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Article ; Online: Peptidylarginine deiminase 2 citrullinates MZB1 and promotes the secretion of IgM and IgA.

Geary, Benjamin / Sun, Bo / Tilvawala, Ronak R / Barasa, Leonard / Tsoyi, Konstantin / Rosas, Ivan O / Thompson, Paul R / Ho, I-Cheng

Frontiers in immunology

2023 Volume 14, Page(s) 1290585

Abstract: Introduction: MZB1 is an endoplasmic reticulum residential protein preferentially expressed in plasma cells, marginal zone and B1 B cells. Recent studies on murine B cells show that it interacts with the tail piece of IgM and IgA heavy chain and ... ...

Abstract	Introduction: MZB1 is an endoplasmic reticulum residential protein preferentially expressed in plasma cells, marginal zone and B1 B cells. Recent studies on murine B cells show that it interacts with the tail piece of IgM and IgA heavy chain and promotes the secretion of these two classes of immunoglobulin. However, its role in primary human B cells has yet to be determined and how its function is regulated is still unknown. The conversion of peptidylarginine to peptidylcitrulline, also known as citrullination, by peptidylarginine deiminases (PADs) can critically influence the function of proteins in immune cells, such as neutrophils and T cells; however, the role of PADs in B cells remains to be elucidated. Method: An unbiased analysis of human lung citrullinome was conducted to identify citrullinated proteins that are enriched in several chronic lung diseases, including rheumatoid arthritis-associated interstitial lung disease (RA-ILD), chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis, compared to healthy controls. Mass spectrometry, site-specific mutagenesis, and western blotting were used to confirm the citrullination of candidate proteins. Their citrullination was suppressed by pharmacological inhibition or genetic ablation of PAD2 and the impact of their citrullination on the function and differentiation of human B cells was examined with enzyme-linked immunosorbent assay, flow cytometry, and co-immunoprecipitation. Results: Citrullinated MZB1 was preferentially enriched in RA-ILD but not in other chronic lung diseases. MZB1 was a substrate of PAD2 and was citrullinated during the differentiation of human plasmablasts. Ablation or pharmacological inhibition of PAD2 in primary human B cells attenuated the secretion of IgM and IgA but not IgG or the differentiation of IgM or IgA-expressing plasmablasts, recapitulating the effect of ablating MZB1. Furthermore, the physical interaction between endogenous MZB1 and IgM/IgA was attenuated by pharmacological inhibition of PAD2. Discussion: Our data confirm the function of MZB1 in primary human plasmablasts and suggest that PAD2 promotes IgM/IgA secretion by citrullinating MZB1, thereby contributing to the pathogenesis of rheumatoid arthritis and RA-ILD.
MeSH term(s)	Humans ; Mice ; Animals ; Protein-Arginine Deiminases/genetics ; Arthritis, Rheumatoid ; Proteins/metabolism ; Idiopathic Pulmonary Fibrosis ; Lung Diseases, Interstitial ; Immunoglobulin A ; Immunoglobulin M
Chemical Substances	Protein-Arginine Deiminases (EC 3.5.3.15) ; Proteins ; Immunoglobulin A ; Immunoglobulin M
Language	English
Publishing date	2023-11-29
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1290585
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Article ; Online: SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8

Celada, Sherly I / Lim, Clarice X / Carisey, Alexandre F / Ochsner, Scott A / Arce Deza, Carlos F / Rexie, Praveen / Poli De Frias, Fernando / Cardenas-Castillo, Rafael / Polverino, Francesca / Hengstschläger, Markus / Tsoyi, Konstantin / McKenna, Neil J / Kheradmand, Farrah / Weichhart, Thomas / Rosas, Ivan O / Van Kaer, Luc / Celada, Lindsay J

Science translational medicine

2023 Volume 15, Issue 713, Page(s) eade2581

Abstract: Sarcoidosis is an interstitial lung disease (ILD) characterized by interferon-γ (IFN-γ) and T-box expressed in T cells (TBET) dysregulation. Although one-third of patients progress from granulomatous inflammation to severe lung damage, the molecular ... ...

Abstract	Sarcoidosis is an interstitial lung disease (ILD) characterized by interferon-γ (IFN-γ) and T-box expressed in T cells (TBET) dysregulation. Although one-third of patients progress from granulomatous inflammation to severe lung damage, the molecular mechanisms underlying this process remain unclear. Here, we found that pharmacological inhibition of phosphorylated SH2-containing protein tyrosine phosphatase-2 (pSHP2), a facilitator of aberrant IFN-γ abundance, decreased large granuloma formation and macrophage infiltration in the lungs of mice with sarcoidosis-like disease. Positive treatment outcomes were dependent on the effective enhancement of TBET ubiquitination within CD8
MeSH term(s)	Humans ; Animals ; Mice ; CD8-Positive T-Lymphocytes ; Sarcoidosis ; Ubiquitination ; Protein Processing, Post-Translational ; Interferon-gamma
Chemical Substances	Interferon-gamma (82115-62-6)
Language	English
Publishing date	2023-09-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.ade2581
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Zs.A 6941: Show issues

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Article ; Online: PAD2-mediated citrullination of Fibulin-5 promotes elastogenesis.

Sun, Bo / Tomita, Beverly / Salinger, Ari / Tilvawala, Ronak R / Li, Ling / Hakami, Hana / Liu, Tao / Tsoyi, Konstantin / Rosas, Ivan O / Reinhardt, Dieter P / Thompson, Paul R / Ho, I-Cheng

Matrix biology : journal of the International Society for Matrix Biology

2021 Volume 102, Page(s) 70–84

Abstract: The formation of elastic fibers is active only in the perinatal period. How elastogenesis is developmentally regulated is not fully understood. Citrullination is a unique form of post-translational modification catalyzed by peptidylarginine deiminases ( ... ...

Abstract	The formation of elastic fibers is active only in the perinatal period. How elastogenesis is developmentally regulated is not fully understood. Citrullination is a unique form of post-translational modification catalyzed by peptidylarginine deiminases (PADs), including PAD1-4. Its physiological role is largely unknown. By using an unbiased proteomic approach of lung tissues, we discovered that FBLN5 and LTBP4, two key elastogenic proteins, were temporally modified in mouse and human lungs. We further demonstrated that PAD2 citrullinated FBLN5 preferentially in young lungs compared to adult lungs. Genetic ablation of PAD2 resulted in attenuated elastogenesis in vitro and age-dependent emphysema in vivo. Mechanistically, citrullination protected FBLN5 from proteolysis and subsequent inactivation of its elastogenic activity. Furthermore, citrullinated but not native FBLN5 partially rescued in vitro elastogenesis in the absence of PAD activity. Our data uncover a novel function of citrullination, namely promoting elastogenesis, and provide additional insights to how elastogenesis is regulated.
MeSH term(s)	Animals ; Calcium-Binding Proteins ; Citrullination ; Elastic Tissue/growth & development ; Extracellular Matrix Proteins/metabolism ; Humans ; Mice ; Protein Processing, Post-Translational ; Protein-Arginine Deiminase Type 2/metabolism ; Protein-Arginine Deiminases/genetics ; Protein-Arginine Deiminases/metabolism ; Proteomics ; Recombinant Proteins/metabolism
Chemical Substances	Calcium-Binding Proteins ; Extracellular Matrix Proteins ; FBLN5 protein, human ; Fbln5 protein, mouse ; Recombinant Proteins ; fibulin ; PADI2 protein, human (EC 3.5.3.15) ; Padi2 protein, mouse (EC 3.5.3.15) ; Protein-Arginine Deiminase Type 2 (EC 3.5.3.15) ; Protein-Arginine Deiminases (EC 3.5.3.15)
Language	English
Publishing date	2021-07-15
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1183793-7
ISSN	1569-1802 ; 0945-053X
ISSN (online)	1569-1802
ISSN	0945-053X
DOI	10.1016/j.matbio.2021.07.001
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Zs.A 1694: Show issues

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Article ; Online: Targeted inhibition of PI3 kinase/mTOR specifically in fibrotic lung fibroblasts suppresses pulmonary fibrosis in experimental models.

Hettiarachchi, Suraj U / Li, Yen-Hsing / Roy, Jyoti / Zhang, Fenghua / Puchulu-Campanella, Estela / Lindeman, Spencer D / Srinivasarao, Madduri / Tsoyi, Konstantin / Liang, Xiaoliang / Ayaub, Ehab A / Nickerson-Nutter, Cheryl / Rosas, Ivan O / Low, Philip S

Science translational medicine

2020 Volume 12, Issue 567

Abstract: Idiopathic pulmonary fibrosis (IPF) is a lethal disease with an average life expectancy of 3 to 5 years. IPF is characterized by progressive stiffening of the lung parenchyma due to excessive deposition of collagen, leading to gradual failure of gas ... ...

Abstract	Idiopathic pulmonary fibrosis (IPF) is a lethal disease with an average life expectancy of 3 to 5 years. IPF is characterized by progressive stiffening of the lung parenchyma due to excessive deposition of collagen, leading to gradual failure of gas exchange. Although two therapeutic agents have been approved from the FDA for IPF, they only slow disease progression with little impact on outcome. To develop a more effective therapy, we have exploited the fact that collagen-producing myofibroblasts express a membrane-spanning protein, fibroblast activation protein (FAP), that exhibits limited if any expression on other cell types. Because collagen-producing myofibroblasts are only found in fibrotic tissues, solid tumors, and healing wounds, FAP constitutes an excellent marker for targeted delivery of drugs to tissues undergoing pathologic fibrosis. We demonstrate here that a low-molecular weight FAP ligand can be used to deliver imaging and therapeutic agents selectively to FAP-expressing cells. Because induction of collagen synthesis is associated with phosphatidylinositol 3-kinase (PI3K) activation, we designed a FAP-targeted PI3K inhibitor that selectively targets FAP-expressing human IPF lung fibroblasts and potently inhibited collagen synthesis. Moreover, we showed that administration of the inhibitor in a mouse model of IPF inhibited PI3K activation in fibrotic lungs, suppressed production of hydroxyproline (major building block of collagen), reduced collagen deposition, and increased mouse survival. Collectively, these studies suggest that a FAP-targeted PI3K inhibitor might be promising for treating IPF.
MeSH term(s)	Animals ; Fibroblasts ; Idiopathic Pulmonary Fibrosis/drug therapy ; Lung ; Mice ; Models, Theoretical ; Phosphatidylinositol 3-Kinases ; TOR Serine-Threonine Kinases
Chemical Substances	TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2020-10-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.aay3724
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Zs.A 6941: Show issues

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Article ; Online: Mesenchymal stromal cell-derived syndecan-2 regulates the immune response during sepsis to foster bacterial clearance and resolution of inflammation.

Han, Junwen / Shi, Yuanyuan / Willis, Gareth / Imani, Jewel / Kwon, Min-Young / Li, Gu / Ayaub, Ehab / Ghanta, Sailaja / Ng, Julie / Hwang, Narae / Tsoyi, Konstantin / El-Chemaly, Souheil / Kourembanas, Stella / Mitsialis, S Alex / Rosas, Ivan O / Liu, Xiaoli / Perrella, Mark A

The FEBS journal

2021 Volume 289, Issue 2, Page(s) 417–435

Abstract: Sepsis is a life-threatening process related to a dysregulated host response to an underlying infection, which results in organ dysfunction and poor outcomes. Therapeutic strategies using mesenchymal stromal cells (MSCs) are under investigation for ... ...

Abstract	Sepsis is a life-threatening process related to a dysregulated host response to an underlying infection, which results in organ dysfunction and poor outcomes. Therapeutic strategies using mesenchymal stromal cells (MSCs) are under investigation for sepsis, with efforts to improve cellular utility. Syndecan (SDC) proteins are transmembrane proteoglycans involved with cellular signaling events including tissue repair and modulating inflammation. Bone marrow-derived human MSCs express syndecan-2 (SDC2) at a level higher than other SDC family members; thus, we explored SDC2 in MSC function. Administration of human MSCs silenced for SDC2 in experimental sepsis resulted in decreased bacterial clearance, and increased tissue injury and mortality compared with wild-type MSCs. These findings were associated with a loss of resolution of inflammation in the peritoneal cavity, and higher levels of proinflammatory mediators in organs. MSCs silenced for SDC2 had a decreased ability to promote phagocytosis of apoptotic neutrophils by macrophages in the peritoneum, and also a diminished capability to convert macrophages from a proinflammatory to a proresolution phenotype via cellular or paracrine actions. Extracellular vesicles are a paracrine effector of MSCs that may contribute to resolution of inflammation, and their production was dramatically reduced in SDC2-silenced human MSCs. Collectively, these data demonstrate the importance of SDC2 for cellular and paracrine function of human MSCs during sepsis.
MeSH term(s)	Animals ; Cell Polarity/genetics ; Cell Polarity/immunology ; Disease Models, Animal ; Extracellular Vesicles/genetics ; Extracellular Vesicles/immunology ; Extracellular Vesicles/microbiology ; Gene Expression Regulation, Developmental/genetics ; Gene Silencing ; Humans ; Immunity/genetics ; Inflammation/genetics ; Inflammation/microbiology ; Inflammation/pathology ; Inflammation/therapy ; Macrophages/immunology ; Macrophages/microbiology ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/metabolism ; Mice ; Neutrophils/immunology ; Neutrophils/microbiology ; Paracrine Communication/genetics ; Phagocytosis/genetics ; Sepsis/genetics ; Sepsis/microbiology ; Sepsis/pathology ; Sepsis/therapy ; Syndecan-2/genetics
Chemical Substances	SDC2 protein, human ; Syndecan-2 (149769-25-5)
Language	English
Publishing date	2021-08-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.16154
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Zs.A 260: Show issues

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Article ; Online: Expression of Stromal Cell-Derived Factor-1 by Mesenchymal Stromal Cells Impacts Neutrophil Function During Sepsis.

Kwon, Min-Young / Ghanta, Sailaja / Ng, Julie / Tsoyi, Konstantin / Lederer, James A / Bronson, Roderick T / El-Chemaly, Souheil / Chung, Su Wol / Liu, Xiaoli / Perrella, Mark A

Critical care medicine

2020 Volume 48, Issue 5, Page(s) e409–e417

Abstract: Objectives: Sepsis results in organ dysfunction caused by a dysregulated host response, in part related to the immune response of a severe infection. Mesenchymal stromal cells are known to modulate the immune response, and expression of stromal cell- ... ...

Abstract	Objectives: Sepsis results in organ dysfunction caused by a dysregulated host response, in part related to the immune response of a severe infection. Mesenchymal stromal cells are known to modulate the immune response, and expression of stromal cell-derived factor-1 regulates mobilization of neutrophils from the bone marrow. We are investigating the importance of stromal cell-derived factor-1 in mesenchymal stromal cells and its role in promoting neutrophil function after the onset of cecal ligation and puncture-induced sepsis. Stromal cell-derived factor-1 expression was silenced in mesenchymal stromal cells, compared with the control scrambled construct mesenchymal stromal cells. Design: Animal study and cell culture. Setting: Laboratory investigation. Subjects: BALB/c mice. Interventions: Polymicrobial sepsis was induced by cecal ligation and puncture. shSCR mesenchymal stromal cells and shSDF-1 mesenchymal stromal cells were delivered by tail vein injections to septic mice. The mice were assessed for survival, bacterial clearance, and the inflammatory response during sepsis in each of the groups. Mesenchymal stromal cells were also assessed for their ability to promote bacterial phagocytosis by neutrophils. Measurements and main results: Injection of shSCR mesenchymal stromal cells after the onset of sepsis led to an increase in mouse survival (70%) at 7 days, whereas survival of mice receiving shSDF-1 mesenchymal stromal cells was significantly diminished (33%). The loss of survival benefit in mice receiving shSDF-1 mesenchymal stromal cells was associated with less efficient bacterial clearance compared with shSCR mesenchymal stromal cells. Although shSCR mesenchymal stromal cells, or their conditioned medium, were able to increase neutrophil phagocytosis of bacteria, this effect was significantly blunted with shSDF-1 mesenchymal stromal cells. Assessment of peritoneal inflammation revealed that neutrophils were significantly increased and more immature in septic mice receiving shSDF-1 mesenchymal stromal cells. This response was associated with hypocellularity and increased neutrophil death in the bone marrow of mice receiving shSDF-1 mesenchymal stromal cells. Conclusions: Expression of stromal cell-derived factor-1 in mesenchymal stromal cells enhances neutrophil function with increased phagocytosis, more efficient clearance of bacteria, and bone marrow protection from depletion of cellular reserves during sepsis.
MeSH term(s)	Animals ; Chemokine CXCL12/pharmacology ; Disease Models, Animal ; Mesenchymal Stem Cells/physiology ; Mice, Inbred BALB C ; Neutrophils/metabolism ; Phagocytosis/drug effects ; Sepsis/mortality ; Sepsis/therapy
Chemical Substances	Chemokine CXCL12
Language	English
Publishing date	2020-03-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	197890-1
ISSN	1530-0293 ; 0090-3493
ISSN (online)	1530-0293
ISSN	0090-3493
DOI	10.1097/CCM.0000000000004244
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Zs.A 1261: Show issues

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Article ; Online: Syndecan-2 regulates PAD2 to exert antifibrotic effects on RA-ILD fibroblasts.

Tsoyi, Konstantin / Esposito, Anthony J / Sun, Bo / Bowen, Ryan G / Xiong, Kevin / Poli, Fernando / Cardenas, Rafael / Chu, Sarah G / Liang, Xiaoliang / Ryter, Stefan W / Beeton, Christine / Doyle, Tracy J / Robertson, Matthew J / Celada, Lindsay J / Romero, Freddy / El-Chemaly, Souheil Y / Perrella, Mark A / Ho, I-Cheng / Rosas, Ivan O

Scientific reports

2022 Volume 12, Issue 1, Page(s) 2847

Abstract: Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) is the most common pulmonary complication of RA, increasing morbidity and mortality. Anti-citrullinated protein antibodies have been associated with the development and progression ... ...

Abstract	Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) is the most common pulmonary complication of RA, increasing morbidity and mortality. Anti-citrullinated protein antibodies have been associated with the development and progression of both RA and fibrotic lung disease; however, the role of protein citrullination in RA-ILD remains unclear. Here, we demonstrate that the expression of peptidylarginine deiminase 2 (PAD2), an enzyme that catalyzes protein citrullination, is increased in lung homogenates from subjects with RA-ILD and their lung fibroblasts. Chemical inhibition or genetic knockdown of PAD2 in RA-ILD fibroblasts attenuated their activation, marked by decreased myofibroblast differentiation, gel contraction, and extracellular matrix gene expression. Treatment of RA-ILD fibroblasts with the proteoglycan syndecan-2 (SDC2) yielded similar antifibrotic effects through regulation of PAD2 expression, phosphoinositide 3-kinase/Akt signaling, and Sp1 activation in a CD148-dependent manner. Furthermore, SDC2-transgenic mice exposed to bleomycin-induced lung injury in an inflammatory arthritis model expressed lower levels of PAD2 and were protected from the development of pulmonary fibrosis. Together, our results support a SDC2-sensitive profibrotic role for PAD2 in RA-ILD fibroblasts and identify PAD2 as a promising therapeutic target of RA-ILD.
MeSH term(s)	Animals ; Anti-Citrullinated Protein Antibodies/genetics ; Arthritis, Rheumatoid/complications ; Arthritis, Rheumatoid/drug therapy ; Arthritis, Rheumatoid/genetics ; Arthritis, Rheumatoid/pathology ; Bleomycin/toxicity ; Citrullination/genetics ; Fibroblasts/metabolism ; Gene Expression Regulation/genetics ; Humans ; Lung/metabolism ; Lung/pathology ; Lung Injury/chemically induced ; Lung Injury/complications ; Lung Injury/genetics ; Lung Injury/pathology ; Mice ; Mice, Transgenic ; Phosphatidylinositol 3-Kinases/genetics ; Protein-Arginine Deiminase Type 2/genetics ; Proto-Oncogene Proteins c-akt/genetics ; Pulmonary Fibrosis/complications ; Pulmonary Fibrosis/drug therapy ; Pulmonary Fibrosis/genetics ; Pulmonary Fibrosis/pathology ; Receptor-Like Protein Tyrosine Phosphatases, Class 3 ; Sp1 Transcription Factor/genetics ; Syndecan-2/genetics
Chemical Substances	Anti-Citrullinated Protein Antibodies ; Sdc2 protein, mouse ; Sp1 Transcription Factor ; SP1 protein, human ; Bleomycin (11056-06-7) ; Syndecan-2 (149769-25-5) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; PTPRJ protein, human (EC 3.1.3.48) ; Receptor-Like Protein Tyrosine Phosphatases, Class 3 (EC 3.1.3.48) ; PADI2 protein, human (EC 3.5.3.15) ; Protein-Arginine Deiminase Type 2 (EC 3.5.3.15)
Language	English
Publishing date	2022-02-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-06678-7
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Article ; Online: Elk-3 is a KLF4-regulated gene that modulates the phagocytosis of bacteria by macrophages.

Tsoyi, Konstantin / Geldart, Adriana M / Christou, Helen / Liu, Xiaoli / Chung, Su Wol / Perrella, Mark A

Journal of leukocyte biology

2015 Volume 97, Issue 1, Page(s) 171–180

Abstract: ETS family proteins play a role in immune responses. A unique member of this family, Elk-3, is a transcriptional repressor that regulates the expression of HO-1. Elk-3 is very sensitive to the effects of inflammatory mediators and is down-regulated by ... ...

Abstract	ETS family proteins play a role in immune responses. A unique member of this family, Elk-3, is a transcriptional repressor that regulates the expression of HO-1. Elk-3 is very sensitive to the effects of inflammatory mediators and is down-regulated by bacterial endotoxin (LPS). In the present study, exposure of mouse macrophages to Escherichia coli LPS resulted in decreased, full-length, and splice-variant isoforms of Elk-3. We isolated the Elk-3 promoter and demonstrated that LPS also decreased promoter activity. The Elk-3 promoter contains GC-rich regions that are putative binding sites for zinc-finger transcription factors, such as Sp1 and KLFs. Mutation of the GC-rich region from bp -613 to -603 blunted LPS-induced down-regulation of the Elk-3 promoter. Similar to the LPS response, coexpression of KLF4 led to repression of Elk-3 promoter activity, whereas coexpression of Sp1 increased activity. ChIP assays revealed that KLF4 binding to the Elk-3 promoter was increased by LPS exposure, and Sp1 binding was decreased. Thus, down-regulation of Elk-3 by bacterial LPS is regulated, in part, by the transcriptional repressor KLF4. Overexpression of Elk-3, in the presence of E. coli bacteria, resulted in decreased macrophage phagocytosis. To determine whether limited expression of HO-1 may contribute to this response, we exposed HO-1-deficient bone marrow-derived macrophages to E. coli and found a comparable reduction in bacterial phagocytosis. These data suggest that down-regulation of Elk-3 and the subsequent induction of HO-1 are important for macrophage function during the inflammatory response to infection.
MeSH term(s)	Animals ; Blotting, Western ; Cell Line ; Chromatin Immunoprecipitation ; Escherichia coli Infections/immunology ; Gene Expression Regulation/immunology ; Heme Oxygenase-1/immunology ; Inflammation/immunology ; Kruppel-Like Transcription Factors/genetics ; Kruppel-Like Transcription Factors/immunology ; Macrophages/immunology ; Membrane Proteins/immunology ; Mice ; Mice, Knockout ; Mutagenesis, Site-Directed ; Phagocytosis/genetics ; Phagocytosis/immunology ; Proto-Oncogene Proteins c-ets/genetics ; Proto-Oncogene Proteins c-ets/immunology ; Real-Time Polymerase Chain Reaction ; Transfection
Chemical Substances	Elk3 protein, mouse ; GKLF protein ; Kruppel-Like Transcription Factors ; Membrane Proteins ; Proto-Oncogene Proteins c-ets ; Heme Oxygenase-1 (EC 1.14.14.18) ; Hmox1 protein, mouse (EC 1.14.14.18)
Language	English
Publishing date	2015-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	605722-6
ISSN	1938-3673 ; 0741-5400
ISSN (online)	1938-3673
ISSN	0741-5400
DOI	10.1189/jlb.4A0214-087R
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