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

Proceedings of the National Academy of Sciences of the United States of America - Tập 116 Số 30 - Trang 15150-15159 - 2019
Salix Boulet1, Jean‐François Daudelin1, Livia Odagiu2,1, Adam‐Nicolas Pelletier2,1, Tae Jin Yun3,4, Sylvie Lesage2,1, Cheolho Cheong3,2,4, Nathalie Labrecque2,5,1
1Laboratory of Immunology, Maisonneuve-Rosemont Hospital Research Center, Montreal, QC H1T 2M4, Canada;
2Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC H3C 3J7, Canada
3Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC H3A 1A3, Canada;
4Laboratory of Cellular Physiology and Immunology, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada
5Département de Médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada

Tóm tắt

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.

Từ khóa


Tài liệu tham khảo

B. Cisse ., Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development. Cell 135, 37–48 (2008).

S. H. Naik ., Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo. Nat. Immunol. 8, 1217–1226 (2007).

T. L. Murphy ., Transcriptional control of dendritic cell development. Annu. Rev. Immunol. 34, 93–119 (2016).

S. Iborra ., Optimal generation of tissue-resident but not circulating memory T cells during viral infection requires crosspriming by DNGR-1+ dendritic cells. Immunity 45, 847–860 (2016).

K. Hildner ., Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 322, 1097–1100 (2008).

A. T. Satpathy ., Notch2-dependent classical dendritic cells orchestrate intestinal immunity to attaching-and-effacing bacterial pathogens. Nat. Immunol. 14, 937–948 (2013).

C. Cheong ., Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209(+) dendritic cells for immune T cell areas. Cell 143, 416–429 (2010).

S. Tamoutounour ., Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin. Immunity 39, 925–938 (2013).

C. Goudot ., Aryl hydrocarbon receptor controls monocyte differentiation into dendritic cells versus macrophages. Immunity 47, 582–596.e6 (2017).

S. Menezes ., The heterogeneity of Ly6Chi monocytes controls their differentiation into iNOS+ macrophages or monocyte-derived dendritic cells. Immunity 45, 1205–1218 (2016).

K. V. Chow, R. M. Sutherland, Y. Zhan, A. M. Lew, Heterogeneity, functional specialization and differentiation of monocyte-derived dendritic cells. Immunol. Cell Biol. 95, 244–251 (2017).

A. T. Satpathy ., Zbtb46 expression distinguishes classical dendritic cells and their committed progenitors from other immune lineages. J. Exp. Med. 209, 1135–1152 (2012).

M. M. Meredith ., Expression of the zinc finger transcription factor zDC (Zbtb46, Btbd4) defines the classical dendritic cell lineage. J. Exp. Med. 209, 1153–1165 (2012).

B. U. Schraml ., Genetic tracing via DNGR-1 expression history defines dendritic cells as a hematopoietic lineage. Cell 154, 843–858 (2013).

C. G. Briseño ., Distinct transcriptional programs control cross-priming in classical and monocyte-derived dendritic cells. Cell Rep. 15, 2462–2474 (2016).

N. Anandasabapathy ., Classical Flt3L-dependent dendritic cells control immunity to protein vaccine. J. Exp. Med. 211, 1875–1891 (2014).

S. A. Mollah ., Flt3L dependence helps define an uncharacterized subset of murine cutaneous dendritic cells. J. Invest. Dermatol. 134, 1265–1275 (2014).

J. Helft ., GM-CSF mouse bone marrow cultures comprise a heterogeneous population of CD11c(+)MHCII(+) macrophages and dendritic cells. Immunity 42, 1197–1211 (2015).

A. Lehtonen ., Gene expression profiling during differentiation of human monocytes to macrophages or dendritic cells. J. Leukoc. Biol. 82, 710–720 (2007).

B. Vander Lugt ., Transcriptional programming of dendritic cells for enhanced MHC class II antigen presentation. Nat. Immunol. 15, 161–167 (2014).

M. A. Pearen, G. E. O. Muscat, Minireview: Nuclear hormone receptor 4A signaling: Implications for metabolic disease. Mol. Endocrinol. 24, 1891–1903 (2010).

S. E. Mullican ., Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. Nat. Med. 13, 730–735 (2007).

R. N. Hanna ., The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes. Nat. Immunol. 12, 778–785 (2011).

I. Shaked ., Transcription factor Nr4a1 couples sympathetic and inflammatory cues in CNS-recruited macrophages to limit neuroinflammation. Nat. Immunol. 16, 1228–1234 (2015).

K. Park ., The transcription factor NR4A3 controls CD103+ dendritic cell migration. J. Clin. Invest. 126, 4603–4615 (2016).

S. H. Naik ., Cutting edge: Generation of splenic CD8+ and CD8- dendritic cell equivalents in Fms-like tyrosine kinase 3 ligand bone marrow cultures. J. Immunol. 174, 6592–6597 (2005).

N. Onai ., Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow. Nat. Immunol. 8, 1207–1216 (2007).

M. E. Kirkling ., Notch signaling facilitates in vitro generation of cross-presenting classical dendritic cells. Cell Rep. 23, 3658–3672.e6 (2018).

E. L. Gautier .; Immunological Genome Consortium, Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012).

J. C. Miller .; Immunological Genome Consortium, Deciphering the transcriptional network of the dendritic cell lineage. Nat. Immunol. 13, 888–899 (2012).

M. Guilliams ., Unsupervised high-dimensional analysis aligns dendritic cells across tissues and species. Immunity 45, 669–684 (2016).

K.-W. Kim ., MHC II+ resident peritoneal and pleural macrophages rely on IRF4 for development from circulating monocytes. J. Exp. Med. 213, 1951–1959 (2016).

N. V. Serbina, T. P. Salazar-Mather, C. A. Biron, W. A. Kuziel, E. G. Pamer, TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19, 59–70 (2003).

M. Neuenhahn ., CD8alpha+ dendritic cells are required for efficient entry of Listeria monocytogenes into the spleen. Immunity 25, 619–630 (2006).

B. T. Edelson ., CD8α(+) dendritic cells are an obligate cellular entry point for productive infection by Listeria monocytogenes. Immunity 35, 236–248 (2011).

T. S. P. Heng, M. W. Painter; Immunological Genome Project Consortium, The immunological genome project: Networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094 (2008).

L. Yang ImmGen microarray phase 1. Gene Expression Omnibus. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE15907. Accessed 27 June 2019.

C. G. Briseno Distinct transcriptional programs control cross-presentation in classical- and monocyte-derived dendritic cells. Gene Expression Omnibus. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE75015. Accessed 27 June 2019.

E. Glasmacher ., A genomic regulatory element that directs assembly and function of immune-specific AP-1-IRF complexes. Science 338, 975–980 (2012).

X. Wu ., Mafb lineage tracing to distinguish macrophages from other immune lineages reveals dual identity of Langerhans cells. J. Exp. Med. 213, 2553–2565 (2016).

H. J. McKenna ., Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 95, 3489–3497 (2000).

A. Mildner ., Genomic characterization of murine monocytes reveals C/EBPβ transcription factor dependence of Ly6C- cells. Immunity 46, 849–862.e7 (2017).

S. Suzuki ., Critical roles of interferon regulatory factor 4 in CD11bhighCD8alpha- dendritic cell development. Proc. Natl. Acad. Sci. U.S.A. 101, 8981–8986 (2004).

S. Bajaña, K. Roach, S. Turner, J. Paul, S. Kovats, IRF4 promotes cutaneous dendritic cell migration to lymph nodes during homeostasis and inflammation. J. Immunol. 189, 3368–3377 (2012).

G. J. Randolph, K. Inaba, D. F. Robbiani, R. M. Steinman, W. A. Muller, Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo. Immunity 11, 753–761 (1999).

S. Boulet N. Labrecque NR4A3 plays a pivotal role in the differentiation of monocyte-derived dendritic cells. Gene Expression Omnibus. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE99837. Deposited 8 June 2017.

Thông tin
Thông tin xuất bản

Proceedings of the National Academy of Sciences of the United States of America

Tập 116 Số 30

15150-15159

Thông tin tác giả