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Recognition of microbe-associated molecular patterns by pattern recognition receptors
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Similar to TLRs, intracellular signaling pathways are shared by multiple CLRs. CLR signaling pathways, however, have not been as well-defined as TLR pathways. The best-described CLR pathway involves DC-associated C-type lectin-1 and -2 (Dectin-1 and Dectin-2) and macrophage-inducible C-type lectin (Mincle), which recognize fungi. These activation CLRs trigger recruitment and phosphorylation of spleen tyrosine kinase (Syk) via immunoreceptor tyrosine-based activation motif (ITAM) that in turn binds CARD9, BCL10, and MALT1 into a complex that activates NF-κB, which induces an array of cell responses, including inflammatory mediator production, and TH17 cell responses. Syk activation also initiates the MAPK pathway and the JNK, p38 and Erk kinase cascade, which regulate cell cycle progression and, consequently, cell proliferation, differentiation, and transformation, as well as inflammatory responses. In contrast to Syk-coupled activation signaling, the SHP-coupled inhibitory CLRs, e.g., DC inhibitory receptor (DCIR), trigger the immunoreceptor tyrosine-based inhibition motif (ITIM). Other CLRs, e.g., DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), mannose receptor (MR), and CD-205, do not have ITAM or ITIM domains and trigger signaling through Raf-1 or yet to be defined pathways.
Endocrine Glands
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Richard A. Peterson, Sundeep Chandra, Mark J. Hoenerhoff
Spontaneous pancreatic islet fibrosis/hemorrhage: In Sprague–Dawley (CD(SD)IGS) rats, pancreatic islet hemorrhage and fibrosis have been shown to occur spontaneously, in males more often than in females and increasing in incidence with age. Spontaneous hemorrhage occurs and is associated with hemosiderin-laden macrophages and an inflammatory cell infiltrate of variable severity. Fibrous connective tissue eventually ensues separating the islet cells (Imaoka et al. 2007). Based upon the apparent sex bias of the lesion, Imaoka et al. investigated the effect of estradiol therapy and ovariectomy. They showed that estrogen treatment in males/ovariectomy in females did not abrogate development of spontaneous islet hemorrhage but did inhibit inflammation and development of islet fibrosis. In males treated with estradiol, there was no change in incidence of islet hemorrhage, although ovariectomy in female rats did cause an increase in incidence of the lesion (Imaoka et al. 2009). Recent data suggest that small moleculeinhibitors of Bruton’s tyrosine kinase (BTK), being developed for oncology and immunology indications, exacerbate this change in Sprague–Dawley rats (Erickson et al. 2017). This change is considered to be rat specific, and non-relevant to human patients. A similar morphologic change is induced by small molecule inhibitors of spleen tyrosine kinase (Syk), being developed for immunology indications. In this case, the authors showed a link between test article-related decreased platelet functional effects and the peri-islet hemorrhage (Long et al. 2016).
Protein Phosphorylation
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
By using antibodies against a portion of amino-terminus of a 40-kDa kinase, a tyrosine kinase of 72 kDa was detected in porcine spleen homogenates.324 The gene encoding this enzyme, syk, was cloned from a porcine spleen library, and its sequence showed the existence of an ORF capable of coding a 628-amino acid polypeptide with a calculated molecular weight of 71,618. The 40-kDa protein kinase is a proteolytic fragment of the 72-kDa holoprotein p72sky or Syk. This protein is a tyrosine kinase of the nonreceptor type. Syk contains two SH2 domains that may play a role in intracellular signaling through binding to phosphotyrosine-containing proteins. Syk is activated by thrombin in porcine platelets and is negatively regulated through Ca2+ signals in the stimulated platelets.325 The major activating pathways evoked by thrombin in platelets are represented by stimulation of phosphatidylinositide metabolism, intracellular mobilization of Ca2+, and activation of protein kinase C. In addition of these pathways, the phosphorylation of platelet proteins on tyrosine by Syk and other kinases may result in the activation of platelet aggregation and secretion.
The ubiquitous role of spleen tyrosine kinase (Syk) in gut diseases: From mucosal immunity to targeted therapy
Published in International Reviews of Immunology, 2022
Wenbin Gong, Peizhao Liu, Tao Zheng, Xiuwen Wu, Yun Zhao, Jianan Ren
Spleen tyrosine kinase (Syk), a cytoplasmic non-receptor protein tyrosine kinase, has essential roles in signal transduction in a variety of cell types. It is involved in signal transduction through associating with receptors that recognize pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), or antigen-Ig complexes [1]. This intracellular kinase transmits and amplifies information by phosphorylating substrates, resulting in a wide range of downstream functional effects, including cell proliferation and differentiation, degranulation, and importantly, inflammatory response [2]. It has been demonstrated that Syk is not only expressed in hematopoietic cells, but also in non-hematopoietic cells [3]. Certainly, the widespread expression of Syk in human tissues means that it plays crucial roles in organs. Syk knock out leads to perinatal death with a severe hemorrhagic phenotype, due to the failed interaction between developing vasculature and lymphatics during embryogenesis [4].
Investigational spleen tyrosine kinase (SYK) inhibitors for the treatment of autoimmune diseases
Published in Expert Opinion on Investigational Drugs, 2022
Su’an Tang, Qinghong Yu, Changhai Ding
Because of wide expression of SYK in hematopoietic cells, it has been found that the level of SYK activation is significantly increased in malignancies. In addition to ADs, SYK inhibitors have also shown promising curative effect in malignancies. For example, piceatannol, a small molecule from the domesticated oilseed Euphorbia lagascae, displays anti-cancer (such as organ-derived tumors and leukemia) properties [100,101]. SRX3207, a novel dual SYK-PI3K inhibitory chemotype, shows abilities in activating anti-tumor immunity in macrophages [102]. Moreover, a newly developed SYK inhibitor, 12 f, has been shown strong anti-tumor activity against solid tumors such as ovarian and lung cancer in experimental studies [103]. However, more clinical studies are needed to further confirm the efficacy and safety of 12 f in cancer patients.
Current and emerging pharmacotherapy for chronic spontaneous Urticaria: a focus on non-biological therapeutics
Published in Expert Opinion on Pharmacotherapy, 2021
Kam Lun Hon, Joyce T. S. Li, Alexander K.C. Leung, Vivian W. Y. Lee
Newer agents are generally considered as add-on therapies to second-generation H1 antihistamines. These novel agents may be able to induce remission, reduce the use of corticosteroid, and improve symptoms in refractory CSU patients. Recent studies aim at identifying new receptors on immune cells that are involved in the pathogenesis of CSU. SYK and Btk are protein tyrosine kinases involved in the signalling of various immune cells. Inhibition of SYK and Btk has been shown to reduce the activation of mast cells and basophils. SYK inhibitors and Btk inhibitors are emerging options in refractory CSU. RCTs on their efficacy and safety in the treatment of CSU are underway. Meanwhile, they are under investigation or already in use for other disease states such as mantle-cell lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis. Experience of use in these fields may provide hints for the long-term safety data. Although serum biomarkers are not usually used as diagnostic indicators for CSU, elevated serum white blood cell count and cytokine level are observed in some patients. Thus, Siglec-8, IL-1, IL-4, IL-5, IL-13, TNF-α, and CD20 may be the possible drug targets for refractory CSU as well [35,133]. There are mAbs and other biologics which target the specific proteins and pathways. They are already available in the market for other indications and are under trial in CSU patients.