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 - 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
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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 -