Innate immune cellular effectors are actively consumed during systemic inflammation but the systemic traffic and the mechanisms that support their replenishment remain unknown. Here we demonstrate that acute systemic inflammation induces the emergent activation of a previously unrecognized system of rapid migration of granulocyte-macrophage progenitors and committed macrophage-dendritic progenitors, but not other progenitors or stem cells, from bone marrow (BM) to regional lymphatic capillaries. The progenitor traffic to the systemic lymphatic circulation is mediated by Ccl19/Ccr7 and is NFkB independent, Traf6/IkB-kinase/SNAP23 activation dependent, and is responsible for the secretion of pre-stored Ccl19 by a subpopulation of CD205+/CD172a+ conventional dendritic cells type 2 (cDC2) and upregulation of BM myeloid progenitor Ccr7 signaling. Mature myeloid Traf6 signaling is anti-inflammatory and necessary for lymph node (LN) myeloid cell development. This report unveils the existence and the mechanistic basis of a very early direct traffic of myeloid progenitors from BM to lymphatics during inflammation.
All data generated or analysed during this study are included in the manuscript and supporting files.
- Jose A Cancelas
- Jose A Cancelas
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol #2019-0041 of Cincinnati Children's Hospital.
Human subjects: Lymphadenopathies from patients were obtained through Institutional Review Board-approved protocols of the Hospital Reina Sofia (Cordoba, Spain), donor informed consent and legal tutor approval in the case of patients younger than 18 years old. Specimens were blindly analyzed through adjudication of unique identifiers.
- Cristina Lo Celso, Imperial College London, United Kingdom
- Received: January 2, 2021
- Accepted: April 7, 2021
- Accepted Manuscript published: April 8, 2021 (version 1)
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