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Fibroblast and Immune Cell Cross Talk in Cardiac Repair
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Stelios Psarras, Georgina Xanthou
Therapeutic infusion of IL-10 in MI induced an M2 alternative type of macrophage activation (73) and directly stimulated fibroblast proliferation and migration. Moreover, fibroblasts from IL-10-administered mice exhibited increased proliferation and a reduced collagen I/III ratio, associated with reduced fibrosis a week following MI (73) (Figure 5.2). Alternative macrophage activation regimes exhibit beneficial effects on fibroblasts and repair mechanisms in other settings as well. Indeed, tribbles pseudokinase-deficient (Trib1) mice show reduced numbers of alternatively activated macrophage populations following MI, and this is accompanied by impaired collagen deposition, leading to catastrophic rupture (69). Whereas IL-4 administration induced alternatively activated macrophages in wt mice, protecting from post-MI rupture, it failed to do so in Trib1−/− mice. However, the protective effects of IL-4 were indirect, involving increased OPN and IL-1α secretion by alternatively activated macrophages that induced myofibroblast formation, reinforcing repair (69) (Figure 5.2).
Maturation, Barrier Function, Aging, and Breakdown of the Blood–Brain Barrier
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Elizabeth de Lange, Ágnes Bajza, Péter Imre, Attila Csorba, László Dénes, Franciska Erdő
It is known that PD is characterized by the progressive loss of select neuronal populations, but prodeath genes mediating the neurodegenerative processes is a novel proposed concept by Aimé et al. (2015). They have proposed a pathway involving tribbles pseudokinase (Trib3), which is a stress-induced gene with proapoptotic activity, to have a role in neuronal death associated with PD (Aimé et al. 2015). For PD, furthermore, Michel et al. (2016) have provided an overview of cell-autonomous mechanisms that are likely to participate in dopamine (DA) cell death in both sporadic and inherited forms of PD. Damage to vulnerable DA neurons may arise from cellular disturbances produced by protein misfolding and aggregation, disruption of autophagic catabolism (a conserved catabolic process that degrades cytoplasmic constituents and organelles in the lysosome), endoplasmic reticulum stress, mitochondrial dysfunction, or loss of calcium homeostasis and where pertinent show how these mechanisms may mutually cooperate to promote neuronal death (Michel et al. 2016).
B-Lymphoblastic Leukemia/Lymphoma
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
JAK mutations are rare in B-ALL (they occur more often in T-ALL). They are most commonly missense mutations at R683 in the pseudokinase domain of JAK2 and are distinct from the JAK2 V617F mutations typical for polycythemia vera and other nonchronic myelogenous leukemia (CML) myeloproliferative neoplasms. Approximately half of CRLF2-rearranged B-ALLs harbor activating JAK1/2 mutations (almost all cases of B-ALL with JAK1/2 mutations harbor concomitant rearrangements of CRLF2).
Abrocitinib: a potential treatment for moderate-to-severe atopic dermatitis
Published in Expert Opinion on Investigational Drugs, 2020
Novin Nezamololama, Erika L. Crowley, Melinda J. Gooderham, Kim Papp
The JAK family of enzymes are intracellular, non-receptor PTKs that primarily transduce cytokine-mediated signals via the JAK-STAT pathway. JAK enzymes are comprised of two near- identical phosphate-transferring domains: one with kinase activity and one without. While the pseudokinase lacks kinase activity, it negatively regulates the activity of the other domain [19,20]. There are four members of the JAK family in mammals, including JAK1, JAK2, JAK3, and tyrosine kinase-2 (TYK2). Distributed on three different chromosomes in humans, the genes of TYK2 and JAK3 are located on chromosome 19, at gene p13.2 and p13.1, respectively, whereas the JAK1 genes are located on chromosome 1p31.3 and JAK2 on chromosome 9p24 [21–23]. JAK1, JAK2, and TYK2 are expressed ubiquitously, while JAK3 is expressed primarily in hematopoietic cells [24,25].
JAK-inhibitors in dermatology: current evidence and future applications
Published in Journal of Dermatological Treatment, 2019
Piotr Ciechanowicz, Adriana Rakowska, Mariusz Sikora, Lidia Rudnicka
JAKs are composed of seven JAK homology (JH) regions which include the catalytically active kinase domain (JH1), the enzymatically inactive pseudokinase domain (JH2), an SH2-like domain (JH3-4), and a divergent four-point-one, ezrin, radixin, moesin (FERM) homology domain (JH4-7) at the amino (N)-terminus (3–5). JAK proteins are attached to self-specific types of cytokine receptors. The function of JAK proteins is associated with the type of cytokine that binds the receptor. STAT family is composed of seven proteins: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6 (6). They play an important role in regulating cell differentiation, survival and apoptosis. Phosphorylated STATs dissociate from the receptor, translocate to the cell nucleus and regulate gene transcription (7). JAK-STAT pathways are involved in signal transduction of numerous dermatologically relevant cytokines such as interferon (IFN)-γ, IFN-α, interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21, IL-5, IL-6, IL-12, IL-13 and IL-23 (8).
Deficiency of the Wnt receptor Ryk causes multiple cardiac and outflow tract defects
Published in Growth Factors, 2018
Kumudhini Kugathasan, Michael M. Halford, Peter G. Farlie, Damien Bates, Darrin P. Smith, You Fang Zhang, James P. Roy, Maria L. Macheda, Dong Zhang, James L. Wilkinson, Margaret L. Kirby, Donald F. Newgreen, Steven A. Stacker
The receptor related to tyrosine kinase (Ryk) is a member of the broader RTK family (Halford et al., 2015; Hovens et al., 1992; Roy et al., 2018), though it is different from most RTKs by having a catalytically inactive PTK domain (Hovens et al., 1992; Mendrola et al., 2013; Murphy et al., 2014; Yoshikawa et al., 2001). Ryk is therefore classified as a pseudokinase (group 2). Ryk contains within its extracellular region a WNT-inhibitory factor (WIF) domain (Patthy, 2000) which binds members of the Wnt family of secreted proteins. Ryk is a high-affinity Wnt receptor and is involved in Wnt/β-catenin signalling (Halford et al., 2013; Liu et al., 2005; Lu et al., 2004; Yoshikawa et al., 2003). Ryk has also been shown to be involved in Wnt/planar cell polarity signalling in the developing mouse cochlea (Andre et al., 2012; Macheda et al., 2012) and other signalling pathways involved in the vasculature (Rao et al., 2015; Skaria et al., 2017).