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Cells
Volume 8
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10.3390/cells8121490
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Article

PC1/3 KD Macrophages Exhibit Resistance to the Inhibitory Effect of IL-10 and a Higher TLR4 Activation Rate, Leading to an Anti-Tumoral Phenotype

by
Franck Rodet
1,*,
Alice Capuz
1,
Bilgehan-Aybike Ozcan
1,
Rémy Le Beillan
1,
Antonella Raffo-Romero
1,
Firas Kobeissy
2,
Marie Duhamel
1 and
Michel Salzet
1,*
1
Université de Lille, Inserm U1192–Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), F-59655 Villeneuve d’Ascq CEDEX, France
2
Department of Psychiatry, McKnight Brain Institute, University of Florida, Gainesville, FL 32611, USA
*
Authors to whom correspondence should be addressed.
Cells 2019, 8(12), 1490; https://doi.org/10.3390/cells8121490
Submission received: 23 October 2019 / Revised: 19 November 2019 / Accepted: 21 November 2019 / Published: 22 November 2019
(This article belongs to the Section Cellular Immunology)
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Abstract

During tumorigenesis, macrophages are recruited by tumors and orientated towards a pro-tumoral phenotype. One of the main anti-tumoral immunotherapy consists of their re-polarization in an anti-tumoral phenotype. We have demonstrated that the inhibition of proprotein convertase 1/3 combined with TLR4 activation in macrophages is a promising strategy. These macrophages display pro-inflammatory and anti-tumoral phenotypes. A hallmark is a stronger activation of the pro-inflammatory NFKB pathway. We believe that this can be explained by a modification of TLR4 expression at the cell surface or MYD88 cleavage since it exhibits a potential cleavage site for proprotein convertases. We tested these hypotheses through immunofluorescence and Western blot experiments. A proteomics study was also performed to test the sensitivity of these macrophages to IL-10. We demonstrated that these macrophages treated with LPS showed a quicker re-expression of TLR4 at the cell surface. The level of MYD88 was also higher when TLR4 was internalized. Moreover, these macrophages were resistant to the pro-tumoral effect of IL-10 and still produced pro-inflammatory factors. This established that the sensitivity to anti-inflammatory molecules and the length of TLR4 desensitization were reduced in these macrophages. Therefore, during antitumoral immunotherapy, a repeated stimulation of TLR4 may reactivate PC1/3 inhibited macrophages even in an anti-inflammatory environment.
Keywords: anti-tumoral immunotherapy; macrophages; proprotein convertase 1/3; TLR4 desensitization; IL-10 pro-tumoral effect anti-tumoral immunotherapy; macrophages; proprotein convertase 1/3; TLR4 desensitization; IL-10 pro-tumoral effect

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MDPI and ACS Style

Rodet, F.; Capuz, A.; Ozcan, B.-A.; Le Beillan, R.; Raffo-Romero, A.; Kobeissy, F.; Duhamel, M.; Salzet, M. PC1/3 KD Macrophages Exhibit Resistance to the Inhibitory Effect of IL-10 and a Higher TLR4 Activation Rate, Leading to an Anti-Tumoral Phenotype. Cells 2019, 8, 1490. https://doi.org/10.3390/cells8121490

AMA Style

Rodet F, Capuz A, Ozcan B-A, Le Beillan R, Raffo-Romero A, Kobeissy F, Duhamel M, Salzet M. PC1/3 KD Macrophages Exhibit Resistance to the Inhibitory Effect of IL-10 and a Higher TLR4 Activation Rate, Leading to an Anti-Tumoral Phenotype. Cells. 2019; 8(12):1490. https://doi.org/10.3390/cells8121490

Chicago/Turabian Style

Rodet, Franck, Alice Capuz, Bilgehan-Aybike Ozcan, Rémy Le Beillan, Antonella Raffo-Romero, Firas Kobeissy, Marie Duhamel, and Michel Salzet. 2019. "PC1/3 KD Macrophages Exhibit Resistance to the Inhibitory Effect of IL-10 and a Higher TLR4 Activation Rate, Leading to an Anti-Tumoral Phenotype" Cells 8, no. 12: 1490. https://doi.org/10.3390/cells8121490

APA Style

Rodet, F., Capuz, A., Ozcan, B.-A., Le Beillan, R., Raffo-Romero, A., Kobeissy, F., Duhamel, M., & Salzet, M. (2019). PC1/3 KD Macrophages Exhibit Resistance to the Inhibitory Effect of IL-10 and a Higher TLR4 Activation Rate, Leading to an Anti-Tumoral Phenotype. Cells, 8(12), 1490. https://doi.org/10.3390/cells8121490

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