Immunoprotective role of an IL-6/gp130/STAT3 signaling axis controlling lymphocyte trafficking during fever

Fever confers a survival benefit in ectotherms and endotherms although it remains the least understood component of the acute phase inflammatory response. Here, we show that immune surveillance of lymphoid organs is improved during lipopolysaccaride- or turpentine-induced fever by increasing lymphocyte trafficking across specialized vascular check-points termed high endothelial venules (HEV). The inflammatory cytokine, interleukin-6 (IL-6), was shown to be dually required for the inductive phase of fever as well as for upregulation of the gatekeeper trafficking molecule ICAM-1 on HEV during the effector phase of a febrile response. To investigate the IL-6 downstream signaling pathways responsible for inducing ICAM-1-dependent trafficking in HEV, we used a reductionist approach in which the core temperature of mice was elevated to a febrile range by administration of whole body hyperthermia (WBH, 39.5-40ºC for 6 hours). Using this system, we identified an autocrine feed-forward loop in which IL-6 produced by HEV acts via an IL-6/soluble IL-6 receptor (sIL-6R)/gp130 signaling platform to enhance lymphocyte trafficking. Comparative analysis of the thermal response in knock-in gp130Y757F/Y757F mice and gp130 DeltaSTAT/DeltaSTAT mice deficient in activation of Ras-Raf-MEK1-ERK1/2 and STAT3/1, respectively, implicated STAT3/1 in the pathway linking IL-6 to induction of ICAM-1-dependent lymphocyte trafficking across HEV. An obligate role for STAT3 during thermal induction of lymphocyte trafficking across HEV was further delineated using STAT1-deficient mice as well as STAT3 E+/- mice in which STAT3 is conditionally deleted only in endothelial cells. Thermally-induced stimulation of trafficking in HEV was further shown to lower the threshold for antigen-driven priming of naive T cells in lymph nodes. While MEK1/ERK1/2 signaling was not required for IL-6-mediated enhancement of lymphocyte trafficking, ERK1/2 activation (independent of gp130 ligation) was necessary for the metalloproteinase-dependent shedding mechanism that restores endothelial ICAM-1 to homeostatic levels during the resolution phase. Taken together, these studies indicate that an IL-6/sIL-6R/gp130/STAT3 axis acts as a highly integrated thermally sensitive alert system that heightens immune surveillance during febrile inflammatory responses. Moreover, identification of selective requirements for STAT3 and ERK1/2 for the regulation of ICAM-1-dependent lymphocyte trafficking provides new insight into novel targets to modulate lymphocyte trafficking during acute and chronic inflammation.