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Fever-range thermal stress promotes lymphocyte trafficking across high endothelial venules via an interleukin 6 trans-signaling mechanism

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Abstract

Fever is an evolutionarily conserved response during acute inflammation, although its physiological benefit is poorly understood. Here we show thermal stress in the range of fever temperatures increased the intravascular display of two 'gatekeeper' homing molecules, intercellular adhesion molecule 1 (ICAM-1) and CCL21 chemokine, exclusively in high endothelial venules (HEVs) that are chief portals for the entry of blood-borne lymphocytes into lymphoid organs. Enhanced endothelial expression of ICAM-1 and CCL21 was linked to increased lymphocyte trafficking across HEVs. A bifurcation in the mechanisms controlling HEV adhesion was demonstrated by evidence that the thermal induction of ICAM-1 but not of CCL21 involved an interleukin 6 trans-signaling pathway. Our findings identify the 'HEV axis' as a thermally sensitive alert system that heightens immune surveillance during inflammation by amplifying lymphocyte trafficking to lymphoid organs.

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Figure 1: Fever-range thermal stress enhances HEV adhesion and homing of lymphocytes to lymphoid organs with HEV structures.
Figure 2: Fever-range thermal stress enhances lymphocyte-HEV interactions.
Figure 3: Fever-range thermal stress selectively increases the expression of ICAM-1 and CCL21 on HEVs.
Figure 4: CCL21 is required for the thermal stimulation of lymphocyte trafficking across HEVs.
Figure 5: ICAM-1 is required for the thermal enhancement of trafficking across HEVs.
Figure 6: IL-6 mediates the thermal stimulation of ICAM-1 expression and homing of lymphocytes across HEVs.
Figure 7: Thermal induction of ICAM-1 and lymphocyte homing does not occur in IL-6-deficient mice.
Figure 8: IL-6 trans signaling mediates the thermal enhancement of ICAM-1 expression and lymphocyte homing in HEVs.

Change history

  • 10 November 2006

    In the version of this article initially published online, the label for the bottom row of Figure 8d is missing. It should read ‘H-IL-6’. The error has been corrected for all versions of the article.

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Acknowledgements

We thank J.D. Black and E.A. Repasky for discussions and comments on the manuscript; M. Miyasaka and T. Tanaka (Osaka University) for antiserum to mouse Duffy antigen–related receptor for chemokines; P.K. Wallace and E.A. Timm for assistance with flow cytometry of leukocyte subsets; and E.L. Hurley for technical support for confocal microscopy. Supported by the US National Institutes of Health (CA79765 and CA094045 to S.S.E.; AI061663 and AI069259 to U.V.A.; DK33886 and CA85580 to H.B.; and CA16056 to Roswell Park Cancer Institute), the Department of Defense (W81XWH-04-1-0354 to Q.C.), the Roswell Park Alliance Foundation (to S.S.E.), the Leukocyte Migration Core of the Harvard Skin Disease Research Center (P30 AR 42689 to U.H.v.A.) and the Deutsche Forschungsgemeinschaft (Bonn, Germany; SFB414, TPB5 to S.R.J.).

Author information

Authors and Affiliations

Authors

Contributions

Q.C. and S.S.E. conceptualized and designed the research; S.S.E. supervised the research; Q.C. did all experiments unless stated otherwise; D.T.F. contributed to the experimental design for quantitative image analysis and did the phenotypic analysis in short-term homing assays and enzyme-linked immunosorbent assay for ICAM-1; K.A.C assisted in immunofluorescence staining and kinetic analysis in short-term homing assays; E.U. contributed to the analysis of ICAM-1 staining; W.-C.W. did frozen-section adherence assays and provided technical assistance for organ retrieval; U.H.v.A. and J.-M.G. helped with intravital microscopy studies; S.R.J. provided the hyper-IL-6 expression construct; H.B. provided recombinant hyper-IL-6 and contributed to discussions regarding IL-6 regulation of lymphocyte trafficking; and all authors contributed to discussions and to the preparation of the manuscript.

Corresponding author

Correspondence to Sharon S Evans.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Fever-range thermal stress enhances lymphocyte homing to lymphoid organs with HEV structures without altering the cellular composition of cells recruited into PLNs. (PDF 107 kb)

Supplementary Fig. 2

Fever-range thermal stress increases lymphocyte-endothelial interactions and ICAM-1 expression in PP HEVs. (PDF 3098 kb)

Supplementary Fig. 3

Fever-range thermal stress did not change total protein abundance of ICAM-1 or CCL21 expression in PLNs. (PDF 155 kb)

Supplementary Fig. 4

ICAM-1 is required for thermal stimulation of lymphocyte trafficking. (PDF 115 kb)

Supplementary Fig. 5

Model for the molecular mechanisms underlying thermal stimulation of lymphocyte trafficking. (PDF 99 kb)

Supplementary Table 1

Summary of vascular adhesion molecule expression in different organs. (PDF 82 kb)

Supplementary Video 1

Lymphocyte-endothelial interactions in nodal venules of a WBH-treated mouse shown by intravital microscopy. (MOV 2916 kb)

Supplementary Methods (PDF 127 kb)

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Chen, Q., Fisher, D., Clancy, K. et al. Fever-range thermal stress promotes lymphocyte trafficking across high endothelial venules via an interleukin 6 trans-signaling mechanism. Nat Immunol 7, 1299–1308 (2006). https://doi.org/10.1038/ni1406

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