Slc44a2 Deficiency Unveils an IFN‐I–Dependent Feedback Control of pDC Egress
Source abstract
Abstract
ABSTRACT Plasmacytoid dendritic cells (pDCs) are a specialized subset of innate immune cells capable of sensing viral nucleic acids and rapidly producing large amounts of type I interferons (IFN‐I). However, excessive IFN‐I production can cause various immunopathogenic conditions. The capacity for IFN‐I production by pDCs is tightly regulated, yet the underlying mechanisms remain incompletely understood. Here, we describe two levels of negative regulatory mechanisms controlling IFN‐I production by pDCs. First, we identified SLC44A2 as a negative regulator of IFN‐I production. Slc44a2 was highly expressed in resting pDCs but significantly downregulated upon activation. Deficiency of Slc44a2 led to excessive IFN‐I production. Mechanistically, SLC44A2 may restrict IFN‐I production by exporting threonine, asparagine, and glutamine, amino acids that we found to be essential for IFN‐I production in pDCs. Second, we uncovered an IFN‐I‐dependent negative feedback mechanism controlling pDC egress. Excessive IFN‐I restrained pDC migration by downregulating CCR2 and CCR5. This feedback was generally observed during viral infections, autoimmune diseases, and in Slc44a2 ‐deficient mice. Taken together, these two regulatory mechanisms are essential for maintaining pDC homeostasis and preventing systemic overactivation of IFN‐I responses.
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Research context
OpenAlex topics: interferon and immune responses · Immunotherapy and Immune Responses · Inflammasome and immune disorders
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
State Key Laboratory of Membrane Biology School of Pharmaceutical Sciences Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education) Tsinghua Medicine Tsinghua University Beijing China
Institute for Immunology School of Basic Medical Sciences Tsinghua Medicine Tsinghua University Beijing China
Tsinghua‐Peking Center for Life Science Beijing China
Department of Central Laboratory The First Hospital of Tsinghua University School of Clinical Medicine Tsinghua Medicine Tsinghua University Beijing China
Bioinformatics Institute (BII) Agency for Science Technology and Research (A*STAR) Singapore
School of Pharmaceutical Sciences Tsinghua Medicine Tsinghua University Beijing China
Beijing Key Laboratory for Immunological Research on Chronic Diseases Beijing China
State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer Innovation Center of Basic Research for Metabolic‐Associated Fatty Liver Disease Ministry of Education of China Tianjian Laboratory of Advanced Biomedical Sciences Academy of Medical sciences Zhengzhou University Zhengzhou Henan China
Funding
National Natural Science Foundation of China
References (100+)
Show source-provided references
1. Dendritic Cell Migration In Health And Disease10.1038/nri.2016.116 ↗
2. Plasmacytoid Dendritic Cells: Sensing Nucleic Acids In Viral Infection And Autoimmune Diseases10.1038/nri2358 ↗
3. IRF‐7 is the Master Regulator Of Type‐I Interferon‐Dependent Immune Responses10.1038/nature03464 ↗
4. Plasmacytoid Pre‐Dendritic Cells (pDC): From Molecular Pathways To Function And Disease Association10.1016/j.semcdb.2018.02.014 ↗
5. Plasmacytoid Dendritic Cells: Key Players In Viral Infections And Autoimmune Diseases10.1016/j.semarthrit.2012.12.026 ↗
6. RUNX2 Mediates Plasmacytoid Dendritic Cell Egress From the Bone Marrow and Controls Viral Immunity10.1016/j.celrep.2016.03.066 ↗
7. Human Lupus Autoantibody–DNA Complexes Activate DCs Through Cooperation of CD32 and TLR910.1172/JCI23025 ↗
8. Genetic Evidence For The Role Of Plasmacytoid Dendritic Cells In Systemic Lupus Erythematosus10.1084/jem.20132522 ↗
9. IFNα Inducible Models of Murine SLE
10. Self‐RNA–Antimicrobial Peptide Complexes Activate Human Dendritic Cells Through TLR7 and TLR810.1084/jem.20090480 ↗
11. Metabolic Deficiencies Underlie Reduced Plasmacytoid Dendritic Cell IFN‐I Production Following Viral Infection10.1038/s41467-025-56603-5 ↗
12. Type I Interferon Negatively Controls Plasmacytoid Dendritic Cell Numbers In Vivo10.1084/jem.20110654 ↗
13. Self‐Renewal and Toll‐Like Receptor Signaling Sustain Exhausted Plasmacytoid Dendritic Cells During Chronic Viral Infection10.1016/j.immuni.2018.03.020 ↗
14. Solute Carrier Transporters: Emerging Central Players In Tumour Immunotherapy10.1016/j.tcb.2021.08.002 ↗
15. Transporters In Vitamin Uptake And Cellular Metabolism: Impacts On Health And Disease10.1093/lifemeta/loaf008 ↗
16. The Choline Transporter‐Like Family SLC44: Properties and Roles In Human Diseases10.1016/j.mam.2012.10.011 ↗
17. Functional Expression of Choline Transporter Like‐Protein 1 (CTL1) and CTL2 in Human Brain Microvascular Endothelial Cells10.1016/j.neuint.2015.12.011 ↗
18. Hair Cell Loss, Spiral Ganglion Degeneration, and Progressive Sensorineural Hearing Loss in Mice With Targeted Deletion of Slc44a2/Ctl210.1007/s10162-015-0547-3 ↗
19. Identification and Characterization of Choline Transporter‐Like Protein 2, an Inner Ear Glycoprotein of 68 and 72 kDa That Is the Target of Antibody‐Induced Hearing Loss10.1523/JNEUROSCI.5063-03.2004 ↗
20. In Vivo Binding and Hearing Loss After Intracochlear Infusion of KHRI‐3 Antibody10.1016/S0378-5955(97)00024-5 ↗
21. SLC44A2 Single Nucleotide Polymorphisms, Isoforms, and Expression: Association With Severity of Meniere's Disease?10.1016/j.ygeno.2016.11.002 ↗
22. Meta‐analysis of 65,734 Individuals Identifies TSPAN15 and SLC44A2 as Two Susceptibility Loci for Venous Thromboembolism10.1016/j.ajhg.2015.01.019 ↗
23. Genome‐Wide Association Analysis Of Self‐Reported Events in 6135 Individuals and 252 827 Controls Identifies 8 Loci Associated With Thrombosis10.1093/hmg/ddw037 ↗
24. The Neutrophil Alloantigen HNA‐3a (5b) is Located On Choline Transporter‐Like Protein 2 and Appears To Be Encoded by an R>Q154 Amino Acid Substitution10.1182/blood-2009-11-248336 ↗
25. Characterization of the Human Neutrophil Alloantigen‐3a10.1038/nm.2070 ↗
26. Characterization of Hemostasis In Mice Lacking The Novel Thrombosis Susceptibility Gene Slc44a210.1016/j.thromres.2018.09.057 ↗
27. The Choline Transporter Slc44a2 Controls Platelet Activation And Thrombosis By Regulating Mitochondrial Function10.1038/s41467-020-17254-w ↗
28. SLC44A2 Deficient Mice Have A Reduced Response In Stenosis But Not In Hypercoagulability Driven Venous Thrombosis10.1111/jth.14835 ↗
29. Activated αIIbβ3 on Platelets Mediates Flow‐Dependent NETosis via SLC44A210.7554/eLife.53353 ↗
30. SLC44A2 Regulates Vascular Smooth Muscle Cell Phenotypic Switching And Aortic Aneurysm10.1172/JCI173690 ↗
31. SLC Transporters As Therapeutic Targets: Emerging Opportunities10.1038/nrd4626 ↗
32. SLC38A2 and Glutamine Signalling in cDC1s Dictate Anti‐Tumour Immunity10.1038/s41586-023-06299-8 ↗
33. PD‐L1 Protects Tumor‐Associated Dendritic Cells From Ferroptosis During Immunogenic Chemotherapy10.1016/j.celrep.2024.114868 ↗
34. Type 1 Interferons Induce Changes in Core Metabolism that Are Critical for Immune Function10.1016/j.immuni.2016.06.006 ↗
35. Metabolic Regulation of Dendritic Cell Differentiation10.3389/fimmu.2019.00410 ↗
36. Evolution of Interferons and Interferon Receptors10.3389/fimmu.2017.00209 ↗
37. Cross‐Species Genome‐Wide Analysis Reveals Molecular And Functional Diversity Of The Unconventional Interferon‐ω Subtype10.3389/fimmu.2019.01431 ↗
38. Gene Synteny, Evolution And Antiviral Activity Of Type I IFNs in a Reptile Species, the Chinese Soft‐Shelled Turtle Pelodiscus Sinensis10.1016/j.dci.2022.104461 ↗
39. SLAMF9 Regulates pDC Homeostasis And Function In Health And Disease10.1073/pnas.1900079116 ↗
40. Frontline Science: AMPK Regulates Metabolic Reprogramming Necessary For Interferon Production In Human Plasmacytoid Dendritic Cells10.1002/JLB.3HI0220-130 ↗
41. Sca‐1 Expression Defines Developmental Stages Of Mouse pDCs That Show Functional Heterogeneity In The Endosomal But Not Lysosomal TLR9 Response10.1002/eji.201343498 ↗
42. Transcription Factor Runx2 Controls The Development And Migration Of Plasmacytoid Dendritic Cells10.1084/jem.20130443 ↗
43. Chemokine Receptor CCR5: Insights Into Structure, Function, And Regulation10.1016/j.cellsig.2004.04.007 ↗
44. Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis10.1371/journal.pone.0158156 ↗
45. Molecular Signature Predictive of Long‐Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development10.1053/j.gastro.2021.12.250 ↗
46. Differential Migration Behavior And Chemokine Production By Myeloid And Plasmacytoid Dendritic Cells10.1016/S0198-8859(02)00755-3 ↗
47. Migration Of Human Blood Dendritic Cells Across Endothelial Cell Monolayers: Adhesion Molecules And Chemokines Involved In Subset‐Specific Transmigration10.1189/jlb.1002516 ↗
48. Chemokines and Chemokine Receptors: Positioning Cells for Host Defense and Immunity10.1146/annurev-immunol-032713-120145 ↗
49. Chemokine And Chemotactic Signals In Dendritic Cell Migration10.1038/s41423-018-0005-3 ↗
50. Role of the Chemokine Receptors CXCR3, CXCR4 and CCR7 in the Intramuscular Recruitment Of Plasmacytoid Dendritic Cells In Dermatomyositis10.1016/j.jneuroim.2018.01.008 ↗
51. Development of Plasmacytoid Dendritic Cells In Bone Marrow Stromal Cell Niches Requires CXCL12‐CXCR4 Chemokine Signaling10.1182/blood-2007-04-084210 ↗
52. Cutting Edge: IFN‐Producing Cells Respond to CXCR3 Ligands in the Presence of CXCL12 and Secrete Inflammatory Chemokines upon Activation10.4049/jimmunol.169.11.6079 ↗
53. CCR7 Essentially Contributes to the Homing of Plasmacytoid Dendritic Cells to Lymph Nodes Under Steady‐State As Well As Inflammatory Conditions10.4049/jimmunol.1002598 ↗
54. Constitutive Plasmacytoid Dendritic Cell Migration to the Splenic White Pulp Is Cooperatively Regulated by CCR7‐ and CXCR4‐Mediated Signaling10.4049/jimmunol.1200802 ↗
55. Differential Requirement for DOCK2 in Migration Of Plasmacytoid Dendritic Cells Versus Myeloid Dendritic Cells10.1182/blood-2007-09-112169 ↗
56. Chemokine Receptor CCR9 Contributes to the Localization of Plasma Cells to the Small Intestine10.1084/jem.20030996 ↗
57. LFA‐1/ICAM‐1 Adhesion Pathway Mediates the Homeostatic Migration of Lymphocytes From Peripheral Tissues Into Lymph Nodes Through Lymphatic Vessels10.3390/biom13081194 ↗
58. Upregulation of VCAM‐1 in Lymphatic Collectors Supports Dendritic Cell Entry And Rapid Migration To Lymph Nodes In Inflammation10.1084/jem.20201413 ↗
59. Osteopontin Expression Is Essential For Interferon‐Α Production By Plasmacytoid Dendritic Cells10.1038/ni1327 ↗
60. Opn: Key Regulator of pDC Interferon Production10.1038/ni0506-441 ↗
61. Decoding Type I and III Interferon Signalling During Viral Infection10.1038/s41564-019-0421-x ↗
62. Regulation of TLR7/9 Signaling In Plasmacytoid Dendritic Cells10.1007/s13238-012-2104-8 ↗
63. Mitochondrial DNA Stress Primes The Antiviral Innate Immune Response10.1038/nature14156 ↗
64. Signaling Pathways of Type I and Type III Interferons and Targeted Therapies in Systemic Lupus Erythematosus10.3390/cells8090963 ↗
65. Histone Deacetylase 3 Contributes To The Antiviral Innate Immunity Of Macrophages By Interacting With FOXK1 to Regulate STAT1/2 Transcription10.1016/j.celrep.2022.110302 ↗
66. Direct Effects of Type I Interferons on Cells of the Immune System10.1158/1078-0432.CCR-10-1114 ↗
67. Decoding Type I and III Interferon Signalling During Viral Infection10.1038/s41564-019-0421-x ↗
68. Choline Transporter‐Like Proteins 1 and 2 are Newly Identified Plasma Membrane And Mitochondrial Ethanolamine Transporters10.1016/j.jbc.2021.100604 ↗
69. Mitochondrial Dysfunction In Choline Deficiency‐Induced Apoptosis In Cultured Rat Hepatocytes10.1016/j.freeradbiomed.2005.04.013 ↗
70. Choline Uptake and Metabolism Modulate Macrophage IL‐1β and IL‐18 Production10.1016/j.cmet.2019.03.011 ↗
71. AMPK‐Activated Protein Kinase Suppresses Ccr2 Expression by Inhibiting the NF‐κB Pathway in RAW264.7 Macrophages10.1371/journal.pone.0147279 ↗
72. Taurine Metabolism Aggravates the Progression of Lupus by Promoting the Function of Plasmacytoid Dendritic Cells10.1002/art.41419 ↗
73. Plasmacytoid Dendritic Cell Activation Is Dependent On Coordinated Expression Of Distinct Amino Acid Transporters10.1016/j.immuni.2021.10.009 ↗
74. OPM Database and PPM Web Server: Resources For Positioning Of Proteins In Membranes10.1093/nar/gkr703 ↗
75. The Chemokine Receptor CCR2 Maintains Plasmacytoid Dendritic Cell Homeostasis10.1016/j.imlet.2017.10.012 ↗
76. Critical Roles for CCR2 and MCP‐3 in Monocyte Mobilization From Bone Marrow And Recruitment To Inflammatory Sites10.1172/JCI29919 ↗
77. Interplay Between CXCR4 and CCR2 Regulates Bone Marrow Exit Of Dendritic Cell Progenitors10.1016/j.celrep.2023.112881 ↗
78. Cc Chemokine Receptor (Ccr)2 Is Required for Langerhans Cell Migration and Localization of T Helper Cell Type 1 (Th1)‐Inducing Dendritic Cells10.1084/jem.192.2.205 ↗
79. Human Dendritic Cell Subsets Undergo Distinct Metabolic Reprogramming for Immune Response10.3389/fimmu.2018.02489 ↗
80. Type I IFN System in the Development and Manifestations of SLE10.1097/BOR.0b013e3283562c3e ↗
81. Asparagine Sensing by TBK1 Controls Its Phase Separation To Drive Antiviral Innate Immune Responses10.1016/j.molcel.2026.01.010 ↗
82. Tolerogenic Phenotype of IFN‐γ–Induced IDO+ Dendritic Cells Is Maintained via an Autocrine IDO–Kynurenine/AhR–IDO Loop10.4049/jimmunol.1502615 ↗
83. Glutamine Promotes Human CD8+ T Cells And Counteracts Imiquimod‐Induced T Cell Hyporesponsiveness10.1016/j.isci.2024.109767 ↗
84. RETRACTED ARTICLE: Metabolic Remodelling Produces Fumarate Via The Aspartate–Argininosuccinate Shunt In Macrophages As An Antiviral Defence10.1038/s41564-025-01985-x ↗
85. TNF and Type I Interferon Crosstalk Controls The Fate And Function Of Plasmacytoid Dendritic Cells10.1038/s41590-025-02234-3 ↗
86. Type I Interferon Dependence Of Plasmacytoid Dendritic Cell Activation And Migration10.1084/jem.20041930 ↗
87. A Mitochondrial STAT3‐Methionine Metabolism Axis Promotes ILC2‐Driven Allergic Lung Inflammation10.1016/j.jaci.2021.12.783 ↗
88. RBP‐J Regulates Homeostasis And Function Of Circulating Ly6Clo Monocytes10.7554/eLife.88135 ↗
89. CD47 Blockade Triggers T Cell–Mediated Destruction Of Immunogenic Tumors10.1038/nm.3931 ↗
90. Cutting Edge: Generation of Splenic CD8+ and CD8− Dendritic Cell Equivalents in Fms‐Like Tyrosine Kinase 3 Ligand Bone Marrow Cultures10.4049/jimmunol.174.11.6592 ↗
91. Encephalomyocarditis Virus 3C Protease Attenuates type I Interferon Production Through Disrupting the TANK–TBK1–IKKε–IRF3 Complex10.1042/BCJ20161037 ↗
92. Plasmacytoid Dendritic Cells Control Homeostasis Of Megakaryopoiesis10.1038/s41586-024-07671-y ↗
93. Minimal, Encapsulated Proteomic‐Sample Processing Applied To Copy‐Number Estimation In Eukaryotic Cells10.1038/nmeth.2834 ↗
94. iProX in 2021: Connecting Proteomics Data Sharing With Big Data10.1093/nar/gkab1081 ↗
95. CD2‐Associated Protein Regulates Plasmacytoid Dendritic Cell Migration, but Is Dispensable for Their Development and Cytokine Production10.4049/jimmunol.1300454 ↗
96. Type I IFN Suppresses Cxcr2 Driven Neutrophil Recruitment Into The Sensory Ganglia During Viral Infection10.1084/jem.20132183 ↗
97. Hes1 Attenuates Type I IFN Responses via VEGF‐C and WDFY110.1084/jem.20180861 ↗
98. LL‐37 Transports Immunoreactive cGAMP to Activate STING Signaling And Enhance Interferon‐Mediated Host Antiviral Immunity10.1016/j.celrep.2022.110880 ↗
99. Diverse Functional Autoantibodies In Patients With COVID‐1910.1038/s41586-021-03631-y ↗
100. The cis‐Regulatory Atlas of the Mouse Immune System10.1016/j.cell.2018.12.036 ↗