Login Register Cart 0
Generic placeholder image

Protein & Peptide Letters

Editor-in-Chief

ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

NMAAP1 Maintains M1 Phenotype in Macrophages Through Binding to IP3R and Activating Calcium-related Signaling Pathways

Author(s): Qihui Liu, Pei Zhu, Shanshan Liu, Mengyan Tang, Yuanxin Wang, Yuan Tian, Zheng Jin, Dong Li and Dongmei Yan*

Volume 26, Issue 10, 2019

Page: [751 - 757] Pages: 7

DOI: 10.2174/0929866526666190503105343

open access plus

Abstract

Background: NMAAP1 plays a role in regulating macrophage differentiation to the M1 type and exerting antitumoral functions. It is not clear what role and mechanism NMAAP1 does play in the reversal of macrophages from M1 to M2.

Methods: We detected the typing of macrophages with high or low expression of NMAAP1 by QPCR and ELISA, and detected the colocalization of NMAAP1 and endogenous IP3R by laser confocal microscopy, and detected the protein expression in cells by Western-blotting.

Results: Our study found that knockdown NMAAP1 in RAW264.7 cells induced macrophage polarization to the M2 type and up-regulation of NMAAP1 in RAW264.7 cells maintain M1 Phenotype even in the presence of IL-4, a stronger inducer of the M2 type. Additionally, Coimmunoprecipitation revealed a protein-protein interaction between NMAAP1 and IP3R and then activates key molecules in the PKC-dependent Raf/MEK/ERK and Ca2+/CaM/CaMKII signaling pathways. Activation of PKC (Thr638/641), ERK1/2 (Thr202/Tyr204) and CaMKII (Thr286) is involved in the regulation of cell differentiation.

Conclusion: NMAAP1 interacts with IP3R, which in turn activates the PKC-dependent Raf/MEK/ERK and Ca2+/CaM/CaMKII signaling pathways. These results provide a new explanation of the mechanism underlying M1 differentiation.

Keywords: NMAAP1, macrophage, M1, polarization, IP3R, Signaling Pathway.

« Previous Next »
Graphical Abstract

[1]
Shapouri-Moghaddam, A.; Mohammadian, S.; Vazini, H.; Taghadosi, M.; Esmaeili, S.A.; Mardani, F.; Seifi, B.; Mohammadi, A.; Afshari, J.T.; Sahebkar, A. Macrophage plasticity, polarization, and function in health and disease. J. Cell. Physiol., 2018, 233(9), 6425-6440.
[http://dx.doi.org/10.1002/jcp.26429] [PMID: 29319160]
[2]
Ruytinx, P.; Proost, P.; Van Damme, J.; Struyf, S.; Struyf, S. Chemokine-induced macrophage polarization in inflammatory conditions. Front. Immunol., 2018, 9, 1930.
[http://dx.doi.org/10.3389/fimmu.2018.01930] [PMID: 30245686]
[3]
Wang, N.; Liang, H.; Zen, K. Molecular mechanisms that influence the macrophage m1-m2 polarization balance. Front. Immunol., 2014, 5, 614.
[http://dx.doi.org/10.3389/fimmu.2014.00614] [PMID: 25506346]
[4]
Mantovani, A.; Sozzani, S.; Locati, M.; Allavena, P.; Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol., 2002, 23(11), 549-555.
[http://dx.doi.org/10.1016/S1471-4906(02)02302-5] [PMID: 12401408]
[5]
Benoit, M.; Desnues, B.; Mege, J.L. Macrophage polarization in bacterial infections. J. Immunol., 2008, 181(6), 3733-3739.
[http://dx.doi.org/10.4049/jimmunol.181.6.3733] [PMID: 18768823]
[6]
Mantovani, A.; Marchesi, F.; Malesci, A.; Laghi, L.; Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol., 2017, 14(7), 399-416.
[http://dx.doi.org/10.1038/nrclinonc.2016.217] [PMID: 28117416]
[7]
Ho, S.H.; So, G.M.; Chow, K.L. Postembryonic expression of Caenorhabditis elegans mab-21 and its requirement in sensory ray differentiation. Dev. Dyn., 2001, 221(4), 422-430.
[http://dx.doi.org/10.1002/dvdy.1161] [PMID: 11500979]
[8]
Liu, Q.; Tian, Y.; Zhao, X.; Jing, H.; Xie, Q.; Li, P.; Li, D.; Yan, D.; Zhu, X. NMAAP1 expressed in BCG-activated macrophage promotes M1 macrophage polarization. Mol. Cells, 2015, 38(10), 886-894.
[http://dx.doi.org/10.14348/molcells.2015.0125] [PMID: 26429502]
[9]
Baxevanis, C.N.; Perez, S.A. Cancer dormancy: A regulatory role for endogenous immunity in establishing and maintaining the tumor dormant state. Vaccines, 2015, 3(3), 597-619.
[http://dx.doi.org/10.3390/vaccines3030597] [PMID: 26350597]
[10]
Kang, B.N.; Ahmad, A.S.; Saleem, S.; Patterson, R.L.; Hester, L.; Doré, S.; Snyder, S.H. Death-associated protein kinase-mediated cell death modulated by interaction with DANGER. J. Neurosci., 2010, 30(1), 93-98.
[http://dx.doi.org/10.1523/JNEUROSCI.3974-09.2010] [PMID: 20053891]
[11]
Roest, G.; La Rovere, R.M.; Bultynck, G. IP 3 receptor properties and function at membrane contact sites. Adv. Exp. Med. Biol., 2017, 981, 149-178.
[http://dx.doi.org/https://doi.org/10.1007/978-3-319-55858-5_7] [PMID: 29594861]
[12]
Thillaiappan, N.B.; Chakraborty, P.; Hasan, G.; Taylor, C.W. IP3 receptors and Ca2+ entry. Biochim. Biophys. Acta Mol. Cell Res., 2019, 1866(7), 1092-1100.
[http://dx.doi.org/https://doi.org/10.1016/j.bbamcr.2018.11.007] [PMID: 30448464]
[13]
Nakanishi, A.; Hatano, N.; Fujiwara, Y.; Sha’ri, A.; Takabatake, S.; Akano, H.; Kanayama, N.; Magari, M.; Nozaki, N.; Tokumitsu, H. AMP-activated protein kinase-mediated feedback phosphorylation controls the Ca2+/calmodulin (CaM) dependence of Ca2+/CaM-dependent protein kinase kinase β. J. Biol. Chem., 2017, 292(48), 19804-19813.
[http://dx.doi.org/10.1074/jbc.M117.805085] [PMID: 28974582]
[14]
Wayman, G.A.; Lee, Y.S.; Tokumitsu, H.; Silva, A.J.; Soderling, T.R. Calmodulin-kinases: modulators of neuronal development and plasticity. Neuron, 2008, 59(6), 914-931.
[http://dx.doi.org/10.1016/j.neuron.2008.08.021] [PMID: 18817731]
[15]
Ayush, O.; Jin, Z.W.; Kim, H.K.; Shin, Y.R. Im, S.Y.; Lee, H.K. Glutamine up-regulates MAPK phosphatase-1 induction via activation of Ca2+→ ERK cascade pathway. Biochem. Biophys. Rep., 2016, 7, 10-19.
[http://dx.doi.org/10.1016/j.bbrep.2016.05.011] [PMID: 28955885]
[16]
Berridge, M.J.; Lipp, P.; Bootman, M.D. The versatility and universality of calcium signalling. Nat. Rev. Mol. Cell Biol., 2000, 1(1), 11-21.
[http://dx.doi.org/10.1038/35036035] [PMID: 11413485]
[17]
Zhivotovsky, B.; Orrenius, S. Calcium and cell death mechanisms: a perspective from the cell death community. Cell Calcium, 2011, 50(3), 211-221.
[http://dx.doi.org/10.1016/j.ceca.2011.03.003] [PMID: 21459443]
[18]
La Rovere, R.M.; Roest, G.; Bultynck, G.; Parys, J.B. Intracellular Ca(2+) signaling and Ca(2+) microdomains in the control of cell survival, apoptosis and autophagy. Cell Calcium, 2016, 60(2), 74-87.
[http://dx.doi.org/10.1016/j.ceca.2016.04.005] [PMID: 27157108]
[19]
Nikolaidis, N.; Chalkia, D.; Watkins, D.N.; Barrow, R.K.; Snyder, S.H.; van Rossum, D.B.; Patterson, R.L. Ancient origin of the new developmental superfamily DANGER. PLoS One, 2007, 2(2), e204-e204.
[http://dx.doi.org/10.1371/journal.pone.0000204] [PMID: 17301879]
[20]
Murray, P.J. Macrophage polarization. Annu. Rev. Physiol., 2017, 79, 541-566.
[http://dx.doi.org/10.1146/annurev-physiol-022516-034339] [PMID: 27813830]
[21]
Zhou, D.; Huang, C.; Lin, Z.; Zhan, S.; Kong, L.; Fang, C.; Li, J. Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways. Cell. Signal., 2014, 26(2), 192-197.
[http://dx.doi.org/10.1016/j.cellsig.2013.11.004] [PMID: 24219909]
[22]
Yang, Y.; Lu, Y.; Han, F.; Chang, Y.; Li, X.; Han, Z.; Xue, M.; Cheng, Y.; Sun, B.; Chen, L. Saxagliptin regulates M1/M2 macrophage polarization via CaMKKβ/AMPK pathway to attenuate NAFLD. Biochem. Biophys. Res. Commun., 2018, 503(3), 1618-1624.
[http://dx.doi.org/10.1016/j.bbrc.2018.07.090] [PMID: 30060948]
[23]
van Rossum, D.B.; Patterson, R.L.; Cheung, K.H.; Barrow, R.K.; Syrovatkina, V.; Gessell, G.S.; Burkholder, S.G.; Watkins, D.N.; Foskett, J.K.; Snyder, S.H. DANGER, a novel regulatory protein of inositol 1,4,5-trisphosphate-receptor activity. J. Biol. Chem., 2006, 281(48), 37111-37116.
[http://dx.doi.org/10.1074/jbc.M608760200] [PMID: 16990268]
[24]
Bandyopadhyay, B.C.; Ong, H.L.; Lockwich, T.P.; Liu, X.; Paria, B.C.; Singh, B.B.; Ambudkar, I.S. TRPC3 controls agonist-stimulated intracellular Ca2+ release by mediating the interaction between inositol 1,4,5-trisphosphate receptor and RACK1. J. Biol. Chem., 2008, 283(47), 32821-32830.
[http://dx.doi.org/10.1074/jbc.M805382200] [PMID: 18755685]
[25]
Kasri, N.N.; Bultynck, G.; Smyth, J.; Szlufcik, K.; Parys, J.B.; Callewaert, G.; Missiaen, L.; Fissore, R.A.; Mikoshiba, K.; de Smedt, H. The N-terminal Ca2+-independent calmodulin-binding site on the inositol 1,4,5-trisphosphate receptor is responsible for calmodulin inhibition, even though this inhibition requires Ca2+. Mol. Pharmacol., 2004, 66(2), 276-284.
[http://dx.doi.org/10.1124/mol.66.2.276] [PMID: 15266018]
[26]
Taylor, C.W.; Prole, D.L. Ca(2+) signalling by IP(3) receptors. Subcell. Biochem., 2012, 59, 1-34.
[http://dx.doi.org/10.1007/978-94-007-3015-1_1] [PMID: 22374086]
[27]
Celada, A.; Schreiber, R.D. Role of protein kinase C and intracellular calcium mobilization in the induction of macrophage tumoricidal activity by interferon-gamma. J. Immunol., 1986, 137(7), 2373-2379.
[PMID: 3093574]
[28]
Leon, C.M.; Barbosa, C.M.; Justo, G.Z.; Borelli, P.; Resende, J.D., Jr; de Oliveira, J.S.; Ferreira, A.T.; Paredes-Gamero, E.J. Requirement for PLCγ2 in IL-3 and GM-CSF-stimulated MEK/ERK phosphorylation in murine and human hematopoietic stem/progenitor cells. J. Cell. Physiol., 2011, 226(7), 1780-1792.
[http://dx.doi.org/10.1002/jcp.22507] [PMID: 21506110]
[29]
Mohanraj, M.; Sekar, P.; Liou, H.H.; Chang, S.F.; Lin, W.W. The mycobacterial adjuvant analogue TDB Attenuates neuro-inflammation via mincle-independent PLC-γ1/PKC/ERK signaling and microglial polarization. Mol. Neurobiol., 2019, 56(2), 1167-1187.
[http://dx.doi.org/10.1007/s12035-018-1135-4] [PMID: 29876879]

Rights & Permissions Print Cite
Article Metrics
45
8
3
2
© 2024 Bentham Science Publishers | Privacy Policy