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

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.

miR-181a Modulation of ERK-MAPK Signaling Sustains DC-SIGN Expression and Limits Activation of Monocyte-Derived Dendritic Cells

“…In line with this, we also did not find miR-181a regulation of Spi1 (PU.1) or IRF4, transcription factors previously associated with lineage commitment of mo-DC versus mo-Mac lineages (Boulet et al, 2019;Goudot et al, 2017;Menezes et al, 2016). We also did not observe changes in frequencies of mo-DCs expressing MMR/CD206, commonly coexpressed with DC-SIGN (van Kooyk and and used interchangeably to mark DC-SIGN + mo-DCs (Boulet et al, 2019;Cheong et al, 2010;Satpathy et al, 2012). Hence, miR-181a, unlike factors such as NR4A3 (Boulet et al, 2019) and AHR (Goudot et al, 2017), is not required for mo-DC differentiation per se but promotes DC-SIGN expression during mo-DC differentiation, revealing a molecular mechanism that directs the expression of DC-SIGN during terminal mo-DC differentiation.…”

“…Similarly, the frequency of total CD11c + CD11b + mo-DCs in the lymph nodes remained equivalent in miR-181a1b1 KO mice versus control mice. In line with this, we also did not find miR-181a regulation of Spi1 (PU.1) or IRF4, transcription factors previously associated with lineage commitment of mo-DC versus mo-Mac lineages (Boulet et al, 2019;Goudot et al, 2017;Menezes et al, 2016). We also did not observe changes in frequencies of mo-DCs expressing MMR/CD206, commonly coexpressed with DC-SIGN (van Kooyk and and used interchangeably to mark DC-SIGN + mo-DCs (Boulet et al, 2019;Cheong et al, 2010;Satpathy et al, 2012).…”

“…We also did not observe changes in frequencies of mo-DCs expressing MMR/CD206, commonly coexpressed with DC-SIGN (van Kooyk and and used interchangeably to mark DC-SIGN + mo-DCs (Boulet et al, 2019;Cheong et al, 2010;Satpathy et al, 2012). Hence, miR-181a, unlike factors such as NR4A3 (Boulet et al, 2019) and AHR (Goudot et al, 2017), is not required for mo-DC differentiation per se but promotes DC-SIGN expression during mo-DC differentiation, revealing a molecular mechanism that directs the expression of DC-SIGN during terminal mo-DC differentiation. mo-DCs among CD45 + HLA-DR + cells in colon mucosa tissues of non-IBD and colitis patients.…”

“…Conversely, mo-Mac cultures induced by M-CSF and IL-6 resemble both DC-SIGN + tumor-associated macrophages (Domínguez-Soto et al, 2011) and macrophages that play a role in graft-versushost disease (Conde et al, 2015). Similar to murine DC-SIGN + mo-DCs (Boulet et al, 2019;Cheong et al, 2010), we show here that human cord blood moP-derived DC-SIGN + mo-DCs are monocyte derived, arising from CD14 + monocytic progenitors, not from CD1a + DC intermediates present in cultures of cord blood CD34 + cells ( Figure S1C). Previously, we performed miRNA profiling and identified specific miRNA expression patterns in different human in vitro-generated DC subsets (Jurkin et al, 2010).…”

Tissue-resident, extravascular CD64-Ly6C-population forms a critical barrier for inflammation in the synovium

“…Since MHCII genes (H2-Eb1, Ab1, Aa, DMb1, DMa) are associated with DCs, we partitioned subpopulations 0, 1 and 3 based on their expression, specifically on H2-Eb1 (Figure S2K-L). As expected, the MHCII + compartment exhibited elevated expression of genes associated with monocyte-derived DCs, including Cd209a, Cd74, and Nr4a3 (Boulet et al, 2019; Ponichtera et al, 2014; Stables et al, 2011) (Figure 2F and Supplemental Table 2C). The remaining non-DC MHCII - fraction was enriched for genes that are known to regulatory function in inflammation, lipid metabolism and angiogenesis including Crip2, Fxyd2, and Rnase4 (Cheung et al, 2011; Li et al, 2013; Mayan et al, 2018) (Figure 2G and Supplemental Table 2C).…”