TY - JOUR
T1 - The persistence of interleukin-6 is regulated by a blood buffer system derived from dendritic cells
AU - Yousif, Ashraf S.
AU - Ronsard, Larance
AU - Shah, Pankaj
AU - Omatsu, Tatsushi
AU - Sangesland, Maya
AU - Bracamonte Moreno, Thalia
AU - Lam, Evan C.
AU - Vrbanac, Vladimir D.
AU - Balazs, Alejandro B.
AU - Reinecker, Hans Christian
AU - Lingwood, Daniel
N1 - Funding Information:
D.L. was supported by NIH grants ( R01AI137057 , DP2DA042422 , R01AI124378 , and R01AI153098 ), the Harvard University Milton Award, and the Gilead Research Scholars Program . H.C.R. was supported by the NIH ( DK068181 , AI113333 , DK043351 , and GM138599) . We thank Lingwood lab technicians past and present for generating the recombinant protein antigens used in this study (Grant Weaver, Rina Villar, Celina Keating, Matthew Smoot, Julia Bals, and Vintus Okonkwo). The authors also thank Masaru Kanekiyo, Jose Ordovas-Montanes, Shiv Pillai, Facundo Batista, Ulrich von Andrian, and Lingwood lab members for helpful discussions. We gratefully acknowledge Michal Grzybek for assistance with figure graphics and Thomas Diefenbach for help with microscopy and imaging analyses.
Funding Information:
D.L. was supported by NIH grants (R01AI137057, DP2DA042422, R01AI124378, and R01AI153098), the Harvard University Milton Award, and the Gilead Research Scholars Program. H.C.R. was supported by the NIH (DK068181, AI113333, DK043351, and GM138599). We thank Lingwood lab technicians past and present for generating the recombinant protein antigens used in this study (Grant Weaver, Rina Villar, Celina Keating, Matthew Smoot, Julia Bals, and Vintus Okonkwo). The authors also thank Masaru Kanekiyo, Jose Ordovas-Montanes, Shiv Pillai, Facundo Batista, Ulrich von Andrian, and Lingwood lab members for helpful discussions. We gratefully acknowledge Michal Grzybek for assistance with figure graphics and Thomas Diefenbach for help with microscopy and imaging analyses. A.S.Y. H.-C.R. A.B.B. and D.L. designed the research. A.S.Y. L.R. P.S. T.O. and V.D.V. performed the research. M.S. T.B.M. and E.C.L. provided reagents. A.S.Y. and D.L. analyzed the data and wrote the paper. The authors declare no competing interests.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/2/9
Y1 - 2021/2/9
N2 - The interleukin-6 (IL-6) membrane receptor and its circulating soluble form, sIL-6R, can be targeted by antibody therapy to reduce deleterious immune signaling caused by chronic overexpression of the pro-inflammatory cytokine IL-6. This strategy may also hold promise for treating acute hyperinflammation, such as observed in coronavirus disease 2019 (COVID-19), highlighting a need to define regulators of IL-6 homeostasis. We found that conventional dendritic cells (cDCs), defined in mice via expression of the transcription factor Zbtb46, were a major source of circulating sIL-6R and, thus, systemically regulated IL-6 signaling. This was uncovered through identification of a cDC-dependent but T cell-independent modality that naturally adjuvants plasma cell differentiation and antibody responses to protein antigens. This pathway was then revealed as part of a broader biological buffer system in which cDC-derived sIL-6R set the in-solution persistence of IL-6. This control axis may further inform the development of therapeutic agents to modulate pro-inflammatory immune reactions. Hyper-elevated IL-6 underscores cytokine storming and chronic inflammatory disorders. Yousif et al. demonstrate that conventional dendritic cells are a major source of sIL-6R, which forms a buffer system that sets the in-solution persistence of IL-6, regulating inflammatory immune reactions.
AB - The interleukin-6 (IL-6) membrane receptor and its circulating soluble form, sIL-6R, can be targeted by antibody therapy to reduce deleterious immune signaling caused by chronic overexpression of the pro-inflammatory cytokine IL-6. This strategy may also hold promise for treating acute hyperinflammation, such as observed in coronavirus disease 2019 (COVID-19), highlighting a need to define regulators of IL-6 homeostasis. We found that conventional dendritic cells (cDCs), defined in mice via expression of the transcription factor Zbtb46, were a major source of circulating sIL-6R and, thus, systemically regulated IL-6 signaling. This was uncovered through identification of a cDC-dependent but T cell-independent modality that naturally adjuvants plasma cell differentiation and antibody responses to protein antigens. This pathway was then revealed as part of a broader biological buffer system in which cDC-derived sIL-6R set the in-solution persistence of IL-6. This control axis may further inform the development of therapeutic agents to modulate pro-inflammatory immune reactions. Hyper-elevated IL-6 underscores cytokine storming and chronic inflammatory disorders. Yousif et al. demonstrate that conventional dendritic cells are a major source of sIL-6R, which forms a buffer system that sets the in-solution persistence of IL-6, regulating inflammatory immune reactions.
KW - antibody response
KW - immune defense
KW - inflammation
KW - regulation
KW - signaling
UR - http://www.scopus.com/inward/record.url?scp=85099063611&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099063611&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2020.12.001
DO - 10.1016/j.immuni.2020.12.001
M3 - Article
C2 - 33357409
AN - SCOPUS:85099063611
SN - 1074-7613
VL - 54
SP - 235-246.e5
JO - Immunity
JF - Immunity
IS - 2
ER -