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Stromal fibroblasts support dendritic cells to maintain IL-23/Th17 responses after exposure to ionizing radiation

Malecka, Anna; Wang, Ounwei; Shah, Sabaria; Sutavani, Ruhcha V.; Spendlove, Ian; Ramage, Judith M.; Greensmith, Julie; Franks, Hester A.; Gough, Michael J.; Saalbach, Anja; Patel, Poulam M.; Jackson, Andrew M.

Authors

Anna Malecka

Ounwei Wang

Sabaria Shah

Ruhcha V. Sutavani

Ian Spendlove

Judith M. Ramage

Julie Greensmith

Hester A. Franks

Michael J. Gough

Anja Saalbach

Poulam M. Patel

Andrew M. Jackson andrew.jackson@nottingham.ac.uk



Abstract

Dendritic cell function is modulated by stromal cells, including fibroblasts. Although poorly understood, the signals delivered through this crosstalk substantially alter dendritic cell biology. This is well illustrated with release of TNF-0/IL-113 from activated dendritic cells, promoting PGE2 secretion from stromal fibroblasts. This instructs dendritic cells to up-regulate IL-23, a key Th17-polarizing cytokine. We previously showed that ionizing radiation inhibited IL-23 production by human dendritic cells in vitro. In the present study, we investigated the hypothesis that dendritic cell-fibroblast crosstalk over¬comes the suppressive effect of ionizing radiation to support appropriately polarized Th17 responses. Radia¬tion (1–6 Gy) markedly suppressed IL-23 secretion by activated dendritic cells (P < 0.0001) without adversely impacting their viability and consequently, inhibited the generation of Th17 responses. Cytokine suppression by ionizing radiation was selective, as there was no effect on IL-10, -6, -10, and -27 or TNF-a and only a modest (11%) decrease in IL-12p70 secretion. Coculture with fibroblasts augmented IL-23 secretion by irradiated dendritic cells and increased Th17 responses. Impor¬tantly, in contrast to dendritic cells, irradiated fibroblasts maintained their capacity to respond to TNF-0/IL-10 and produce PGE2, thus providing the key intermediary signals for successful dendritic cell-fibroblasts crosstalk. In summary, stromal fibroblasts support Th17-polarizing cytokine production by dendritic cells that would other¬wise be suppressed in an irradiated microenvironment. This has potential ramifications for understanding the immune response to local radiotherapy. These findings underscore the need to account for the impact of microenvironmental factors, including stromal cells, in understanding the control of immunity. J. Leukoc. Biol. 100: 000–000; 2016.

Journal Article Type Article
Publication Date 2016-08
Journal Journal of Leukocyte Biology
Print ISSN 0741-5400
Electronic ISSN 1938-3673
Publisher Society for Leukocyte Biology
Peer Reviewed Peer Reviewed
Volume 100
Issue 2
Pages 381-389
APA6 Citation Malecka, A., Wang, O., Shah, S., Sutavani, R. V., Spendlove, I., Ramage, J. M., …Jackson, A. M. (2016). Stromal fibroblasts support dendritic cells to maintain IL-23/Th17 responses after exposure to ionizing radiation. Journal of Leukocyte Biology, 100(2), 381-389. https://doi.org/10.1189/jlb.3A1015-474R
DOI https://doi.org/10.1189/jlb.3A1015-474R
Publisher URL http://www.jleukbio.org/content/100/2/381
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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