CD169+ macrophages orchestrate plasmacytoid dendritic cell arrest and retention for optimal priming in the bone marrow of malaria-infected mice
- Albert Einstein College of Medicine, United States
Abstract
Plasmacytoid dendritic cells (pDC) are the most potent producer of type I interferon (IFN), but how pDC are primed in vivo is poorly defined. Using a mouse model of severe malaria, we have previously established that upon priming by CD169+ macrophages (MP), pDC initiate type I IFN-I secretion in the bone marrow (BM) of infected mice via cell-intrinsic TLR7 sensing and cell-extrinsic STING sensing. Herein we show that CD169+ MP and TLR7-sensing are both required for pDC arrest during priming, suggesting CD169+ MP are the source of TLR7 ligands. We establish that TLR7 sensing in pDC and chemotaxis are both required for pDC arrest and functional communication with CD169+ MP in the BM. Lastly, we demonstrate that STING-sensing in CD169+ MP control pDC initiation of type I IFN production while also regulating pDC clustering and retention/egress from the BM. Collectively, these results link pDC acquisition of type I IFN secreting capacity with changes in their motility, homing and interactions with CD169+ MP during infection. Thus, targeting this cellular interaction may help modulate type I IFN to improve outcomes of microbial infections and autoimmune diseases.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for all figures. There is no restriction of access.
Article and author information
Author details
Funding
NIAID (AI103666)
- David Fooksman
- Gregoire Lauvau
NIH (T32 GM7288 ; F31 HL147470)
- Jamie Moore-Fried
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was carried out in strict accordance with the recommendations by the animal use committee at the Albert Einstein College of Medicine under protocol number #20171113 and 00001375. The institution is accredited by the "American Association for the Use of Laboratory Animals" (DHEW Publication No. (NIH) 78-23, Revised 1978), and accepts as mandatory the NIH "Principles for the Use of Animals". All efforts were made to minimize suffering and provide humane treatment to the animals included in the study.
Copyright
© 2022, Moore-Fried et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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CD169+ macrophages orchestrate plasmacytoid dendritic cell arrest and retention for optimal priming in the bone marrow of malaria-infected mice
eLife 11:e78873.
https://doi.org/10.7554/eLife.78873
Further reading
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- Immunology and Inflammation
- Medicine
Background:
Individuals with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display clear signs of immune dysregulation, including high rates of autoimmunity and severe complications from infections. Although it is well established that T21 causes increased interferon responses and JAK/STAT signaling, elevated autoantibodies, global immune remodeling, and hypercytokinemia, the interplay between these processes, the clinical manifestations of DS, and potential therapeutic interventions remain ill defined.
Methods:
We report a comprehensive analysis of immune dysregulation at the clinical, cellular, and molecular level in hundreds of individuals with DS, including autoantibody profiling, cytokine analysis, and deep immune mapping. We also report the interim analysis of a Phase II clinical trial investigating the safety and efficacy of the JAK inhibitor tofacitinib through multiple clinical and molecular endpoints.
Results:
We demonstrate multi-organ autoimmunity of pediatric onset concurrent with unexpected autoantibody-phenotype associations in DS. Importantly, constitutive immune remodeling and hypercytokinemia occur from an early age prior to autoimmune diagnoses or autoantibody production. Analysis of the first 10 participants to complete 16 weeks of tofacitinib treatment shows a good safety profile and no serious adverse events. Treatment reduced skin pathology in alopecia areata, psoriasis, and atopic dermatitis, while decreasing interferon scores, cytokine scores, and levels of pathogenic autoantibodies without overt immune suppression.
Conclusions:
JAK inhibition is a valid strategy to treat autoimmune conditions in DS. Additional research is needed to define the effects of JAK inhibition on the broader developmental and clinical hallmarks of DS.
Funding:
NIAMS, Global Down Syndrome Foundation.
Clinical trial number:
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- Immunology and Inflammation
- Medicine
Metabolic abnormalities associated with liver disease have a significant impact on the risk and prognosis of cholecystitis. However, the underlying mechanism remains to be elucidated. Here, we investigated this issue using Wilson’s disease (WD) as a model, which is a genetic disorder characterized by impaired mitochondrial function and copper metabolism. Our retrospective clinical study found that WD patients have a significantly higher incidence of cholecystitis and a poorer prognosis. The hepatic immune cell landscape using single-cell RNA sequencing showed that the tissue immune microenvironment is altered in WD, mainly a major change in the constitution and function of the innate immune system. Exhaustion of natural killer (NK) cells is the fundamental factor, supported by the upregulated expression of inhibitory receptors and the downregulated expression of cytotoxic molecules, which was verified in clinical samples. Further bioinformatic analysis confirmed a positive correlation between NK cell exhaustion and poor prognosis in cholecystitis and other inflammatory diseases. The study demonstrated dysfunction of liver immune cells triggered by specific metabolic abnormalities in WD, with a focus on the correlation between NK cell exhaustion and poor healing of cholecystitis, providing new insights into the improvement of inflammatory diseases by assessing immune cell function.
