A Model of iPSC-Derived Macrophages with TNFAIP3 Overexpression Reveals the Peculiarities of TNFAIP3 Protein Expression and Function in Human Macrophages.

Autor: Sheveleva O; Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Vavilova Str., 26, 119334 Moscow, Russia., Protasova E; Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Vavilova Str., 26, 119334 Moscow, Russia., Nenasheva T; Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Vavilova Str., 26, 119334 Moscow, Russia., Butorina N; Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Vavilova Str., 26, 119334 Moscow, Russia., Melnikova V; Laboratory of Comparative Developmental Physiology, Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Vavilova Str., 26, 119334 Moscow, Russia., Gerasimova T; Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Vavilova Str., 26, 119334 Moscow, Russia., Sakovnich O; Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Vavilova Str., 26, 119334 Moscow, Russia., Kurinov A; Laboratory of Regeneration Problems, Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Vavilova Str., 26, 119334 Moscow, Russia., Grigor'eva E; Laboratory of Developmental Epigenetics, Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Lavrentyev Ave., 10, 630090 Novosibirsk, Russia., Medvedev S; Laboratory of Developmental Epigenetics, Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Lavrentyev Ave., 10, 630090 Novosibirsk, Russia., Lyadova I; Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Vavilova Str., 26, 119334 Moscow, Russia.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2023 Aug 16; Vol. 24 (16). Date of Electronic Publication: 2023 Aug 16.
DOI: 10.3390/ijms241612868
Abstrakt: Macrophages play a crucial role in the development and control of inflammation. Understanding the mechanisms balancing macrophage inflammatory activity is important to develop new strategies for treating inflammation-related diseases. TNF-α-induced protein 3 (TNFAIP3, A20) is a negative regulator of intracellular inflammatory cascades; its deficiency induces hyper-inflammatory reactions. Whether A20 overexpression can dampen macrophage inflammatory response remains unclear. Here, we generated human-induced pluripotent stem cells with tetracycline-inducible A20 expression and differentiated them into macrophages (A20-iMacs). A20-iMacs displayed morphology, phenotype, and phagocytic activity typical of macrophages, and they displayed upregulated A20 expression in response to doxycycline. A20 overexpression dampened the A20-iMac response to TNF-α, as shown by a decreased expression of IL1B and IL6 mRNA. A dynamic analysis of A20 expression following the generation of A20-iMacs and control iMacs showed that the expression declined in iMacs and that iMacs expressed a lower molecular weight form of the A20 protein (~70 kDa) compared with less differentiated cells (~90 kDa). A low-level expression of A20 and the predominance of a low-molecular-weight A20 form were also characteristic of monocyte-derived macrophages. The study for the first time developed a model for generating macrophages with an inducible expression of a target gene and identified the peculiarities of A20 expression in macrophages that likely underlie macrophage preparedness for inflammatory reactivity. It also suggested the possibility of mitigating inflammatory macrophage responses via A20 overexpression.
Databáze: MEDLINE
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