The role of macrophage migration inhibitory factor (MIF) in autoimmunity is underscored by data showing that common functional polymorphisms in MIF are associated with disease susceptibility or ...clinical severity. MIF can regulate glucocorticoid-mediated immunosuppression and has a prominent function in cell survival signalling. Further specific functions of MIF are now being defined in different autoimmune diseases and MIF-targeted biologic therapeutics are in early-stage clinical trials. The unique structure of MIF is also directing the development of small-molecule MIF antagonists. Together, these efforts could provide a means of selectively intervening in pathogenesis and overcoming MIF-related genetic susceptibility to many rheumatic diseases.
Targeting fibrocytes in autoimmunity Bucala, Richard J
Proceedings of the National Academy of Sciences - PNAS,
02/2022, Letnik:
119, Številka:
5
Journal Article
Sepsis and septic shock are among the leading causes of death in intensive care units worldwide. Numerous studies on their pathophysiology have revealed an imbalance in the inflammatory network ...leading to tissue damage, organ failure, and ultimately, death. Cytokines are important pleiotropic regulators of the immune response, which have a crucial role in the complex pathophysiology underlying sepsis. They have both pro- and anti-inflammatory functions and are capable of coordinating effective defense mechanisms against invading pathogens. On the other hand, cytokines may dysregulate the immune response and promote tissue-damaging inflammation. In this review, we address the current knowledge of the actions of pro- and anti-inflammatory cytokines in sepsis pathophysiology as well as how these cytokines and other important immunomodulating agents may be therapeutically targeted to improve the clinical outcome of sepsis.
The proinflammatory cytokine macrophage migration inhibitory factor (MIF) has been shown to be cardioprotective under various pathological conditions. However, the underlying mechanisms still remain ...elusive. In this study, we revealed that MIF deficiency overtly exacerbated abdominal aorta constriction–induced cardiac hypertrophy and contractile anomalies. MIF deficiency interrupted myocardial autophagy in hypertrophied hearts. Rapamycin administration mitigated the exacerbated hypertrophic responses in MIF mice. Using the phenylephrine-induced hypertrophy in vitro model in H9C2 myoblasts, we confirmed that MIF governed the activation of AMP-activated protein kinase–mammalian target of rapamycin–autophagy cascade. Confocal microscopic examination demonstrated that MIF depletion prevented phenylephrine-induced mitophagy in H9C2 myoblasts. Myocardial Parkin, an E3 ubiquitin ligase and a marker for mitophagy, was significantly upregulated after sustained pressure overload, the effect of which was prevented by MIF knockout. Furthermore, our data exhibited that levels of MIF, AMP-activated protein kinase activation, and autophagy were elevated concurrently in human failing hearts. These data indicate that endogenous MIF regulates the mammalian target of rapamycin signaling to activate autophagy to preserve cardiac geometry and protect against hypertrophic responses.
Molecules that link innate and adaptive immunity and regulate immune response in health and disease are now the focus of many studies. This review discusses CD74 and its ligand macrophage migration ...inhibitory factor (MIF), and their central position in linking these two components of the immune response by controlling survival of macrophages and B cells.
Background
The gingival epithelium protects periodontal tissues and the alveolar bone by maintaining a steady state of regulated inflammatory surveillance, also known as healthy homeostasis. ...Accordingly, the repertoire of receptors present within the gingival epithelium showcases its ability to recognize microbial colonization and contribute to bacterial sensing. Macrophage migration inhibitory factor (MIF) is one of many cytokines that are expressed in this protective state and is involved in neutrophil regulation. However, its role in the maintenance of healthy gingival tissue has not been described.
Methods
Gingival tissues from wild‐type (WT) and Mif knock‐out (KO) mice were stained for neutrophils and three key neutrophil chemoattractants: MIF, Gro‐α/CXCL1, and Gro‐β/CXCL2 in the junctional epithelium (JE). In addition, gene silencing studies were performed using gingival epithelial cells (GECs) to examine the role of MIF on transcription of key bacterial recognition receptors Toll‐like receptors (TLR)‐1, ‐2, ‐4, ‐6, ‐9 and interleukin‐1 receptors (IL‐1R1 and IL‐1R2) in response to oral bacterial stimulation.
Results
WT murine gingival tissues demonstrated high expression of MIF in the JE. In Mif KO mice, despite the significant reduction of Gro‐α/CXCL1 and Gro‐β/CXCL2, there was a slight increase in neutrophils. Gene silencing experiments showed that MIF down‐regulated the mRNA expression of TLR4, IL‐1R1, and IL‐1R2 in GEC, in addition to decreasing secreted IL‐8/CXCL8 in response to bacteria.
Conclusions
MIF regulates the expression of TLR4, IL‐1Rs, and IL‐8/CXCL8, components that are all involved in maintaining oral health. Our data demonstrate that MIF is a significant contributor to the maintenance of healthy oral homeostasis.
The pleiotropic effects of macrophage migration inhibitory factor (MIF) place it in a central position in the immunopathogenesis of many diseases. Here we discuss the current understanding of MIF's ...role and highlight it as a potential link between inflammatory activation and malignant progression.
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