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Phagocytosis By Human Neutrophils
Published in Hans H. Gadebusch, Phagocytes and Cellular Immunity, 2020
Recently, Najjar150,151 and his colleagues have described a phagocytosis-stimulating peptide called “tuftsin.” This does not really qualify as an opsonin because it does not act on the bacteria, but it appears to act directly on the neutrophil. According to Najjar, the spleen secretes a large gamma globulin named leukokinin into the blood stream. An enzyme present in the membrane of the neutrophil (leukokininase) cleaves a small tetrapeptide (tuftsin) from the large molecule. Trypsin can substitute for the natural protease in the neutrophilic membrane. Tuftsin has been isolated, characterized, and synthesized.152 It is a hormone-like peptide with the composition thr-lys-pro-arg. Najjar has reported that tuftsin acts to double or triple the rate of phagocytosis by normal cells, increase cell survival in vitro, and increase cell migration as determined by the capillary tube method.151,152 Another group has reported that tuftsin increases the reduction of nitroblue tetrazolium dye by normal resting cells153 (discussed in Stage IID), and has recently verified the effect of tuftsin on the uptake of particles.154 Finally, tuftsin appears to be absent in splenectomized patients, and several patients have been described with congenital tuftsin deficiencies associated with recurrent bacterial infections.155
Inflammation
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
In the next phase, phagocytes recognize the area of damaged tissue. Specific antibodies coat bacteria which are mainly IgGj and IgG3 with intact Fc and Fab portions. 214,373 This process is called opsonization. C reactive proteins, α- and β-globulins, C3a- and C5a-peptide fragments also exert coating ability.206,441 Tuftsin, a tetrapeptide with the amino acid sequence THR-LYS-PRO-ARG, also acts on phagocytes.332 Tuftsin is a natural macrophage activator and exerts immunogenic, antineoplastic, and other effects. Following the association, the particles become attached to neutrophils by receptors for the Fc region of IgG.409
Advances in engineering and delivery strategies for cytokine immunotherapy
Published in Expert Opinion on Drug Delivery, 2023
Margaret Bohmer, Yonger Xue, Katarina Jankovic, Yizhou Dong
Multiple polymer-based NPs have been implemented in a specific body of research involving the manipulation of macrophage phenotypes. Alginate, a natural and biocompatible polymer, was used to make nanoparticles to deliver IL-10 plasmid DNA for arthritis treatment [130]. Alginate is a random block copolymer composed of (1 → 4) linked β-d-mannuronic acid and α-l-guluronic acid monomers. Tuftsin, a peptide that targets macrophages, was then added to the surface of the alginate-based NPs. Tuftsin targets macrophages by binding to their Fc and neuropilin-1 receptors, stimulating phagocytosis. These tuftsin-modified alginate NPs delivered the IL-10 plasmids to macrophages and induced phenotype repolarization from M1 (pro-inflammatory) to M2 (anti-inflammatory) [130]. A different study sought to induce the reverse phenomenon: macrophage reversal from M2 to M1 to promote inflammation in the TME. Tumor-associated macrophages (TAM) originate from circulatory monocytes that tumors attract by producing chemotactic signals. When these monocytes differentiate into macrophages, an M2-like phenotype is favored due to numerous microenvironmental conditions, such as cytokines, growth factors, and hypoxia [131]. Poly(β-amino ester)-based NPs were synthesized to encapsulate IL-12 [132]. Poly(β-amino ester) NPs were chosen because they are pH sensitive and dissociate at weakly acidic conditions, such as that in the TME as a result of hypoxia and high lactic acid production [133]. These IL-12-loaded NPs converted tumor-associated macrophages from M2 to M1 type [132].
Legumain protease-sheddable PEGylated, tuftsin-modified nanoparticles for selective targeting to tumour-associated macrophages
Published in Journal of Drug Targeting, 2022
De-Sheng Liang, Zu-Jun Wen, Jia-Hui Wang, Fang-Fang Zhu, Feng Guo, Jian-Liang Zhou, Jian-Jun Xu, Hai-Jun Zhong
Tuftsin, a natural macrophage activator tetrapeptide (Thr-Lys-Pro-Arg, TKPR), was derived from the Fc portion of the heavy chain of leukophilic immunoglobulin G (IgG) [16]. It has been demonstrated that tuftsin can bind to the Fc receptor of macrophages and augment a broad spectrum of activities related to immune system function, such as phagocytosis, immunogenic response, and bactericidal activities [17–19]. Taking advantage of its phagocytosis-stimulating effect, researchers have developed various tuftsin-directed nanocarriers for improved treatment of macrophage-based infections. Jain and co-workers [20] successfully built tuftsin-modified alginate nanoparticles as a macrophage-targeted DNA delivery system to treat rheumatoid arthritis. Horváti et al. [21] recently built tuftsin-decorated Pluronic F127/poly(L-lactic-co-glycolic acid) (PLGA) nanoparticles for targeting tuberculosis, and demonstrated that the tuftsin-directed nanocarriers significantly increased macrophage internalisation, which showed great promise in the application of macrophage-targeted delivery.
Multimodal imaging and photothermal synergistic immunotherapy of retinoblastoma with tuftsin-loaded carbonized MOF nanoparticles
Published in Drug Delivery, 2022
Hongmi Zou, Meng Li, Xing Li, Wendi Zheng, Hongyu Kuang, Menglei Wang, Wenli Zhang, Haitao Ran, Huafeng Ma, Xiyuan Zhou
Studies have shown that TAMs participate in the immunosuppression, invasion and metastasis of tumors. Macrophages can be roughly divided into M1 macrophages and M2 macrophages according to their functions. M1 macrophages are involved in the inflammatory response, pathogen clearance, and antitumor immunity. In contrast, M2 macrophages affect the anti-inflammatory response and wound healing and have protumor properties (Mantovani et al., 2007; Komohara et al., 2016). Guerra et al. found that hydrogels embedded in M1 macrophages upregulated nitrite and tumor necrosis factor α (TNF-α) to activate caspase-3 to induce tumor apoptosis, resulting in apoptosis of HCC cells in vivo and in vitro (Guerra et al., 2017). Piña et al. found that Rb tumor load increased after M1 TAMs were reduced (Piña et al., 2010). The study of Yamamoto N's team suggested that macrophages activated by PTII have a killing effect on Rb tumors, and the activation of macrophages is the first step of immune enhancement (Yamamoto et al., 1994). Therefore, M1-type macrophage induction may be an effective immunotherapy approach for Rb. Tuftsin is a tetrapeptide with the structure of Thr-Lys-Pro-Arg. Its activity is mainly related to the function of the immune system, especially macrophages, which can activate macrophages and induce M1-type polarization (Fridkin & Najjar, 1989). However, tuftsin has a short half-life in vivo and is easily hydrolyzed, which limits its application and development (An et al., 2014). The encapsulation of MOF nanoparticles can prevent rapid hydrolysis of the drug in vivo, thus improving its efficacy.