Metallothionein as an Anti-Inflammatory Mediator

The integration of knowledge concerning the regulation of MT, a highly conserved, low molecular weight, cystein-rich metalloprotein, on its proposed functions is necessary to clarify how MT affects cellular processes. MT expression is induced/enhanced in various tissues by a number of physiological mediators. The cellular accumulation of MT depends on the availability of cellular zinc derived from the diet. MT modulates the binding and exchange/transport of heavy metals such as zinc, cadmium, or copper under physiological conditions and cytoprotection from their toxicities, and the release of gaseous mediators such as hydroxyl radicals or nitric oxide. In addition, MT reportedly affects a number of cellular processes, such as gene expression, apoptosis, proliferation, and differentiation. Given the genetic approach, the apparently healthy status of MT-deficient mice argues against an essential biological role for MT; however, this molecule may be critical in cells/tissues/organs in times of stress, since MT expression is also evoked/enhanced by various stresses. In particular, because metallothionein (MT) is induced by inflammatory stress, its roles in inflammation are implied. Also, MT expression in various organs/tissues can be enhanced by inflammatory stimuli, implicating in inflammatory diseases. In this paper, we review the role of MT of various inflammatory conditions.

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On the Role of the Immunoproteasome in Protein Homeostasis

Cells ◽

10.3390/cells10113216 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3216

Author(s):

Michael Basler ◽

Marcus Groettrup

Keyword(s):

Inflammatory Diseases ◽

Protein Homeostasis ◽

Cellular Processes ◽

Inflammatory Conditions ◽

Histocompatibility Complex ◽

Species Formation ◽

Preclinical Animal Models ◽

Prime Function ◽

In Cells

Numerous cellular processes are controlled by the proteasome, a multicatalytic protease in the cytosol and nucleus of all eukaryotic cells, through regulated protein degradation. The immunoproteasome is a special type of proteasome which is inducible under inflammatory conditions and constitutively expressed in hematopoietic cells. MECL-1 (β2i), LMP2 (β1i), and LMP7 (β5i) are the proteolytically active subunits of the immunoproteasome (IP), which is known to shape the antigenic repertoire presented on major histocompatibility complex (MHC) class I molecules. Furthermore, the immunoproteasome is involved in T cell expansion and inflammatory diseases. In recent years, targeting the immunoproteasome in cancer, autoimmune diseases, and transplantation proved to be therapeutically effective in preclinical animal models. However, the prime function of standard proteasomes and immunoproteasomes is the control of protein homeostasis in cells. To maintain protein homeostasis in cells, proteasomes remove proteins which are not properly folded, which are damaged by stress conditions such as reactive oxygen species formation, or which have to be degraded on the basis of regular protein turnover. In this review we summarize the latest insights on how the immunoproteasome influences protein homeostasis.

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Hyperferritinaemia: An Iron Sword of Autoimmunity

Current Pharmaceutical Design ◽

10.2174/1381612825666190709202804 ◽

2019 ◽

Vol 25 (27) ◽

pp. 2909-2918 ◽

Cited By ~ 4

Author(s):

Joanna Giemza-Stokłosa ◽

Md. Asiful Islam ◽

Przemysław J. Kotyla

Keyword(s):

Immune Response ◽

Macrophage Activation ◽

Inflammatory Diseases ◽

Acute Phase Reactant ◽

Catastrophic Antiphospholipid Syndrome ◽

Inflammatory Conditions ◽

Phase Reactant ◽

Signalling Molecule ◽

Cytokine Synthesis

Background:: Ferritin is a molecule that plays many roles being the storage for iron, signalling molecule, and modulator of the immune response. Methods:: Different electronic databases were searched in a non-systematic way to find out the literature of interest. Results:: The level of ferritin rises in many inflammatory conditions including autoimmune disorders. However, in four inflammatory diseases (i.e., adult-onset Still’s diseases, macrophage activation syndrome, catastrophic antiphospholipid syndrome, and sepsis), high levels of ferritin are observed suggesting it as a remarkable biomarker and pathological involvement in these diseases. Acting as an acute phase reactant, ferritin is also involved in the cytokine-associated modulator of the immune response as well as a regulator of cytokine synthesis and release which are responsible for the inflammatory storm. Conclusion:: This review article presents updated information on the role of ferritin in inflammatory and autoimmune diseases with an emphasis on hyperferritinaemic syndrome.

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The Role of N6-Methyladenosine (m6A) Methylation Modifications in Hematological Malignancies

Cancers ◽

10.3390/cancers14020332 ◽

2022 ◽

Vol 14 (2) ◽

pp. 332

Author(s):

Yan Zhao ◽

Hongling Peng

Keyword(s):

Bone Marrow ◽

Pluripotent Stem Cells ◽

Rna Splicing ◽

Messenger Rna ◽

Hematologic Malignancies ◽

Cellular Processes ◽

Proliferation And Differentiation ◽

Regulatory Functions ◽

Increased Susceptibility

Epigenetics is identified as the study of heritable modifications in gene expression and regulation that do not involve DNA sequence alterations, such as DNA methylation, histone modifications, etc. Importantly, N6-methyladenosine (m6A) methylation modification is one of the most common epigenetic modifications of eukaryotic messenger RNA (mRNA), which plays a key role in various cellular processes. It can not only mediate various RNA metabolic processes such as RNA splicing, translation, and decay under the catalytic regulation of related enzymes but can also affect the normal development of bone marrow hematopoiesis by regulating the self-renewal, proliferation, and differentiation of pluripotent stem cells in the hematopoietic microenvironment of bone marrow. In recent years, numerous studies have demonstrated that m6A methylation modifications play an important role in the development and progression of hematologic malignancies (e.g., leukemia, lymphoma, myelodysplastic syndromes [MDS], multiple myeloma [MM], etc.). Targeting the inhibition of m6A-associated factors can contribute to increased susceptibility of patients with hematologic malignancies to therapeutic agents. Therefore, this review elaborates on the biological characteristics and normal hematopoietic regulatory functions of m6A methylation modifications and their role in the pathogenesis of hematologic malignancies.

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Increased and prolonged inflammation and angiogenesis in delayed-type hypersensitivity reactions elicited in the skin of thrombospondin-2–deficient mice

Blood ◽

10.1182/blood.v99.2.538 ◽

2002 ◽

Vol 99 (2) ◽

pp. 538-545 ◽

Cited By ~ 52

Author(s):

Bernhard Lange-Asschenfeldt ◽

Wolfgang Weninger ◽

Paula Velasco ◽

Themis R. Kyriakides ◽

Ulrich H. von Andrian ◽

...

Keyword(s):

Inflammatory Diseases ◽

Angiogenesis Inhibitor ◽

Dermal Fibroblasts ◽

Delayed Type Hypersensitivity ◽

Hypersensitivity Reactions ◽

Wild Type ◽

Edema Formation ◽

Inflammatory Infiltration ◽

Deficient Mice

Abstract Angiogenesis and enhanced microvascular permeability are hallmarks of a large number of inflammatory diseases. Although up-regulation of proangiogenic factors such as vascular endothelial growth factor and interleukin-8 have been previously reported in inflamed tissue, the biologic role of endogenous inhibitors of angiogenesis in inflammation has remained unclear. To investigate the biologic role of the potent angiogenesis inhibitor thrombospondin-2 (TSP-2) in the control of cutaneous inflammation, delayed-type hypersensitivity reactions were elicited in the ear skin of wild-type and TSP-2–deficient mice by topical sensitization and challenge with oxazolone. Cutaneous TSP-2 expression was up-regulated in the inflamed skin of wild-type mice, predominantly in dermal fibroblasts and microvessels. Lack of TSP-2 resulted in a significantly enhanced inflammatory response with increased angiogenesis, edema formation, and inflammatory infiltration. Ear swelling and inflammation persisted for more than 2 weeks in TSP-2–deficient mice, as compared with 1 week in wild-type mice. Although baseline vascular permeability was unchanged, significantly enhanced microvascular leakage was found in the inflamed skin of TSP-2–deficient mice. Moreover, the fraction of rolling leukocytes was significantly increased in the untreated skin of TSP-2–deficient mice. These results reveal an important role of TSP-2 in limiting the extent and the duration of edema formation, angiogenesis, and inflammatory cell infiltration during acute and chronic inflammation.

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Progranulin aggravates pulmonary immunopathology during influenza virus infection

Thorax ◽

10.1136/thoraxjnl-2018-211916 ◽

2018 ◽

Vol 74 (3) ◽

pp. 305-308 ◽

Cited By ~ 6

Author(s):

Qin Luo ◽

Xingxing Yan ◽

Hongmei Tu ◽

Yibing Yin ◽

Ju Cao

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Inflammatory Diseases ◽

Influenza Virus Infection ◽

Epithelial Barrier ◽

Alveolar Epithelial ◽

Cytokines And Chemokines ◽

Deficient Mice ◽

Experimental Influenza

Progranulin (PGRN) exerts multiple functions in various inflammatory diseases. However, the role of PGRN in the pathogenesis of virus infection is unknown. Here, we demonstrated that PGRN production was up-regulated in clinical and experimental influenza, which contributed to the deleterious inflammatory response after influenza virus infection in mice. PGRN-deficient mice were protected from influenza virus-induced lung injury and mortality. Decreased mortality was associated with significantly reduced influx of neutrophils and monocytes/macrophages, release of cytokines and chemokines, and permeability of the alveolar–epithelial barrier without affecting viral clearance. Our findings suggest that PGRN exacerbates pulmonary immunopathology during influenza virus infection.

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Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies

International Journal of Molecular Sciences ◽

10.3390/ijms21239203 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9203

Author(s):

Renée Daams ◽

Ramin Massoumi

Keyword(s):

Tissue Homeostasis ◽

Spinocerebellar Ataxias ◽

Adult Tissue ◽

Signalling Molecules ◽

Cellular Processes ◽

Protein Map ◽

Mitogen Activated Protein ◽

And Function ◽

Deficient Mice

The Wnt signalling pathway is a central communication cascade between cells to orchestrate polarity and fate during development and adult tissue homeostasis in various organisms. This pathway can be regulated by different signalling molecules in several steps. One of the coordinators in this pathway is Nemo-like kinase (NLK), which is an atypical proline-directed serine/threonine mitogen-activated protein (MAP) kinase. Very recently, NLK was established as an essential regulator in different cellular processes and abnormal NLK expression was highlighted to affect the development and progression of various diseases. In this review, we focused on the recent discoveries by using NLK-deficient mice, which show a phenotype in the development and function of organs such as the lung, heart and skeleton. Furthermore, NLK could conduct the function and differentiation of cells from the immune system, in addition to regulating neurodegenerative diseases, such as Huntington’s disease and spinocerebellar ataxias. Overall, generations of NLK-deficient mice have taught us valuable lessons about the role of this kinase in certain diseases and development.

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Signal transducer and activator of transcription proteins in leukemias

Blood ◽

10.1182/blood-2002-04-1204 ◽

2003 ◽

Vol 101 (8) ◽

pp. 2940-2954 ◽

Cited By ~ 221

Author(s):

Mustafa Benekli ◽

Maria R. Baer ◽

Heinz Baumann ◽

Meir Wetzler

Keyword(s):

Potential Role ◽

Cellular Transformation ◽

Leukemia Cells ◽

Signal Transducer ◽

Stat Proteins ◽

Cellular Processes ◽

Proliferation And Differentiation ◽

Stat Signaling ◽

Novel Therapeutic Strategies

Abstract Signal transducer and activator of transcription (STAT) proteins are a 7-member family of cytoplasmic transcription factors that contribute to signal transduction by cytokines, hormones, and growth factors. STAT proteins control fundamental cellular processes, including survival, proliferation, and differentiation. Given the critical roles of STAT proteins, it was hypothesized that inappropriate or aberrant activation of STATs might contribute to cellular transformation and, in particular, leukemogenesis. Constitutive activation of mutated STAT3 has in fact been demonstrated to result in transformation. STAT activation has been extensively studied in leukemias, and mechanisms of STAT activation and the potential role of STAT signaling in leukemogenesis are the focus of this review. A better understanding of mechanisms of dysregulation of STAT signaling pathways may serve as a basis for designing novel therapeutic strategies that target these pathways in leukemia cells.

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Osteoclasts contribute to early development of chronic inflammation by promoting dysregulated hematopoiesis and myeloid skewing

10.1101/2020.12.09.418137 ◽

2020 ◽

Author(s):

Maria-Bernadette Madel ◽

Lidia Ibáñez ◽

Thomas Ciucci ◽

Julia Halper ◽

Majlinda Topi ◽

...

Keyword(s):

Inflammatory Diseases ◽

Myeloid Differentiation ◽

Chronic Colitis ◽

Therapeutic Blockade ◽

Hematopoietic Stem ◽

Chronic Inflammatory Diseases ◽

Promising Target ◽

Proliferation And Differentiation ◽

Early Phases

ABSTRACTIncreased myelopoiesis is a hallmark of many chronic inflammatory diseases. However, the mechanisms involved in the myeloid skewing of hematopoiesis upon inflammation are still incompletely understood. Here, we identify an unexpected role of bone-resorbing osteoclasts in promoting hematopoietic stem cell (HSC) proliferation and differentiation towards myeloipoiesis in the early phases of chronic colitis. RNAseq analysis revealed that osteoclasts in colitis differ from control ones and overexpress genes involved in the remodeling of HSC niches. We showed that colitic osteoclasts modulate the interaction of HSCs with their niche and promote myeloid differentiation. Increased osteoclast activity was correlated with an augmentation of myelopoiesis in patients with chronic colitis. Therapeutic blockade of osteoclasts reduced HSC proliferation and myeloid skewing and resulted in a decreased inflammation and severity of colitis. Together, these data identify osteoclasts as potent regulators of HSCs and promising target in chronic colitis.

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Abstract 307: Role of Epsins in Regulating LPS-Induced Sepsis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.307 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Satish Pasula ◽

Megan L Brophy ◽

Kandice L Tessneer ◽

Scott Hahn ◽

John McManus ◽

...

Keyword(s):

Inflammatory Responses ◽

Tissue Injury ◽

Lethal Dose ◽

Surface Protein ◽

Inflammatory Conditions ◽

Fundamental Information ◽

Subsequent Degradation ◽

Surface Protein Expression ◽

Deficient Mice

Background: Sepsis is caused by a deleterious host response to infection, which is primarily responsible for further injury of host tissue and cause of organ dysfunction. However, the underlying regulatory mechanisms are still not fully understood. Our goal is to define the novel role of epsins in regulating sepsis. Methods and Results: We engineered global (iDKO) and endothelial cell-specific (EC-iDKO) epsin deficient mice. When treated with lethal dose of LPS, epsin deficient mice were completely protected from LPS-induced septic death. These mice also exhibited decreased expression of tissue damage biomarkers and recruitment of neutrophils and macrophages to lungs compared to wild type (WT) suggesting that epsin deficiency mitigates sepsis induced tissue injury. Epsin deficiency further reduced expression of proinflammatory cytokines and adhesion molecules in the lungs suggesting that loss of epsin attenuates LPS-induced inflammatory responses. TAT complex production was also decreased in iDKO mice compared to WT indicating diminished coagulation and thrombin production. Knocking down of epsins in HUVECs resulted in reduced cell surface Tissue Factor (TF) expression. Loss of epsin in mice protected against loss of Thrombomodulin (TM), which is downregulated by sepsis. Mechanistically, loss of epsin inhibited LPS-induced TM internalization, while LPS treatment induced the ubiquitination of TM. Furthermore, co-IP of full length epsin 1 or epsin 1 without the UIM domain and TM demonstrated that UIM is required for the interaction between epsin 1 and TM. Collectively, we show that epsin-deficiency upregulates TM surface protein expression by preventing its internalization and subsequent degradation and inhibits heightened TF expression and activation under chronic inflammatory conditions such as that induced by LPS exposure. Conclusions: Our findings demonstrate that epsins play a key role in regulating coagulation and provide fundamental information on the modulation of the ratio of TM/TF in various thrombotic diseases including sepsis. Furthermore, we demonstrate loss of epsin protects mice against LPS-induced sepsis, suggesting a crucial role for epsins in promoting the development of LPS-induced sepsis.

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Generation and Analysis of Mice Lacking the Chemokine Fractalkine

Molecular and Cellular Biology ◽

10.1128/mcb.21.9.3159-3165.2001 ◽

2001 ◽

Vol 21 (9) ◽

pp. 3159-3165 ◽

Cited By ~ 102

Author(s):

Donald N. Cook ◽

Shu-Cheng Chen ◽

Lee M. Sullivan ◽

Denise J. Manfra ◽

Maria T. Wiekowski ◽

...

Keyword(s):

Gene Disruption ◽

Surface Marker ◽

Wild Type ◽

Blood Leukocytes ◽

Targeted Gene Disruption ◽

Behavioral Abnormalities ◽

Inflammatory Stimuli ◽

Membrane Bound ◽

Deficient Mice

ABSTRACT Fractalkine (CX3CL1) is the first described chemokine that can exist either as a soluble protein or as a membrane-bound molecule. Both forms of fractalkine can mediate adhesion of cells expressing its receptor, CX3CR1. This activity, together with its expression on endothelial cells, suggests that fractalkine might mediate adhesion of leukocytes to the endothelium during inflammation. Fractalkine is also highly expressed in neurons, and its receptor, CX3CR1, is expressed on glial cells. To determine the biologic role of fractalkine, we used targeted gene disruption to generate fractalkine-deficient mice. These mice did not exhibit overt behavioral abnormalities, and histologic analysis of their brains did not reveal any gross changes compared to wild-type mice. In addition, these mice had normal hematologic profiles except for a decrease in the number of blood leukocytes expressing the cell surface marker F4/80. The cellular composition of their lymph nodes did not differ significantly from that of wild-type mice. Similarly, the responses offractalkine −/− mice to a variety of inflammatory stimuli were indistinguishable from those of wild-type mice.

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