IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation

McLoughlin, Rachel Mary, Jenkins, Brendan J., Grail, Dianne, Williams, Anwen Sian ORCID: https://orcid.org/0000-0001-6118-020X, Fielding, Ceri Alan ORCID: https://orcid.org/0000-0002-5817-3153, Parker, Clare R., Ernst, Matthias, Topley, Nicholas and Jones, Simon Arnett ORCID: https://orcid.org/0000-0001-7297-9711 2005. IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation. Proceedings of the National Academy of Sciences of the United States of America (PNAS) ISSN 1091-6490 102 (27) , pp. 9589-9594. 10.1073/pnas.0501794102

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Abstract

Interleukin (IL)-6 signaling through its soluble receptor (IL-6 transsignaling) directs transition between innate and acquired immune responses by orchestrating the chemokine-directed attraction and apoptotic clearance of leukocytes. Through analysis of mononuclear cell infiltration in WT and IL-6-deficient mice during peritoneal inflammation, we now report that IL-6 selectively governs T cell infiltration by regulating chemokine secretion (CXCL10, CCL4, CCL5, CCL11, and CCL17) and chemokine receptor (CCR3, CCR4, CCR5, and CXCR3) expression on the CD3+ infiltrate. Although blockade of IL-6 trans-signaling prevented chemokine release, chemokine receptor expression remained unaltered suggesting that this response is regulated by IL-6 itself. To dissect the signaling events promoting T cell migration, inflammation was established in knock-in mice expressing mutated forms of the universal signal-transducing element for IL-6-related cytokines gp130. In mice (gp130Y757F/Y757F) deficient in SHP2 and SOCS3 binding, but presenting hyperactivation of STAT1/3, T cell recruitment and CCL5 expression was enhanced. Conversely, both of these parameters were suppressed in mice with ablated gp130-mediated STAT1/3 activation (gp130DeltaSTAT/DeltaSTAT). T cell migration was related to STAT3 activity, because monoallelic deletion of Stat3 in gp130(Y757F/Y757F) mice (gp130Y757F/Y757F:Stat3+/-) corrected the exaggerated responses observed in gp130Y757F/Y757F mice. Consequently, STAT3 plays a defining role in IL-6-mediated T cell migration.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Publisher:	National Academy of Sciences
ISSN:	1091-6490
Last Modified:	17 Oct 2022 08:29
URI:	https://orca.cardiff.ac.uk/id/eprint/275

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