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Proc Natl Acad Sci U S A. 2019 Jul 8. pii: 201821296. doi: 10.1073/pnas.1821296116. [Epub ahead of print]

The orphan nuclear receptor NR4A3 controls the differentiation of monocyte-derived dendritic cells following microbial stimulation.

Author information

1
Laboratory of Immunology, Maisonneuve-Rosemont Hospital Research Center, Montreal, QC H1T 2M4, Canada.
2
Département de Microbiologie, Infectiologie, et Immunologie, Université de Montréal, Montréal, QC H3C 3J7, Canada.
3
Laboratory of Cellular Physiology and Immunology, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada.
4
Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC H3A 1A3, Canada.
5
Laboratory of Immunology, Maisonneuve-Rosemont Hospital Research Center, Montreal, QC H1T 2M4, Canada; nathalie.labrecque@umontreal.ca.
6
Département de Médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada.

Abstract

In response to microbial stimulation, monocytes can differentiate into macrophages or monocyte-derived dendritic cells (MoDCs) but the molecular requirements guiding these possible fates are poorly understood. In addition, the physiological importance of MoDCs in the host cellular and immune responses to microbes remains elusive. Here, we demonstrate that the nuclear orphan receptor NR4A3 is required for the proper differentiation of MoDCs but not for other types of DCs. Indeed, the generation of DC-SIGN+ MoDCs in response to LPS was severely impaired in Nr4a3 -/- mice, which resulted in the inability to mount optimal CD8+ T cell responses to gram-negative bacteria. Transcriptomic analyses revealed that NR4A3 is required to skew monocyte differentiation toward MoDCs, at the expense of macrophages, and allows the acquisition of migratory characteristics required for MoDC function. Altogether, our data identify that the NR4A3 transcription factor is required to guide the fate of monocytes toward MoDCs.

KEYWORDS:

LPS response; NR4A3; monocyte-derived dendritic cells; nuclear receptors

PMID:
31285338
DOI:
10.1073/pnas.1821296116

Conflict of interest statement

The authors declare no conflict of interest.

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