SIGNR1-Negative Red Pulp Macrophages Protect against Acute Streptococcal Sepsis after Leishmania donovani-Induced Loss of Marginal Zone Macrophages

Kirby, Alun C.; Beattie, Lynette; Maroof, Asher; Rooijen, Nico van; Kaye, Paul M.

doi:10.2353/ajpath.2009.090258

Cited by 30 publications

(29 citation statements)

References 38 publications

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“…This may help explain the inconsistent reports in the literature of individual markers on specific cell populations. For example, RPMs have been variably reported to lack or express CD11b (11,19,23,37). FIHC is thus particularly useful in identifying cell populations, including monocytes/neutrophils (CD11b high ), MZMs (SIGN-R1 ϩ ), MMMs (CD169 ϩ ), and RPMs (F4/80 ϩ ), because it is based on anatomic location, cellular morphology, and expression of cell population-specific markers.…”

Section: Discussionmentioning

confidence: 99%

Trafficking and Replication Patterns Reveal Splenic Macrophages as Major Targets of Dengue Virus in Mice

Prestwood

May

Plummer

et al. 2012

J Virol

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Human postmortem studies of natural dengue virus (DENV) infection have reported systemically distributed viral antigen. Although it is widely accepted that DENV infects mononuclear phagocytes, the sequence in which specific tissues and cell types are targeted remains uncharacterized. We previously reported that mice lacking alpha/beta and gamma interferon receptors permit high levels of DENV replication and show signs of systemic disease (T. R. Prestwood et al., J. Virol. 82:8411-8421, 2008). Here we demonstrate that within 6 h, DENV traffics to and replicates in both CD169؉ and SIGN-R1 ؉ macrophages of the splenic marginal zone or draining lymph node, respectively, following intravenous or intrafootpad inoculation. Subsequently, high levels of replication are detected in F4/80 ؉ splenic red pulp macrophages and in the bone marrow, lymph nodes, and Peyer's patches. Intravenously inoculated mice begin to succumb to dengue disease 72 h after infection, at which time viral replication occurs systemically, except in lymphoid tissues. In particular, high levels of replication occur in CD68؉ macrophages of the kidneys, heart, thymus, and gastrointestinal tract. Over the course of infection, proportionately large quantities of DENV traffic to the liver and spleen. However, late during infection, viral trafficking to the spleen decreases, while trafficking to the liver, thymus, and kidneys increases. The present study demonstrates that macrophage populations, initially in the spleen and other lymphoid tissues and later in nonlymphoid tissues, are major targets of DENV infection in vivo.T he four serotypes of dengue virus (DENV1 to DENV4) belong to the Flaviviridae family and cause a mosquito-borne febrile illness in more than 50 million people per year. In nearly 500,000 cases per year, individuals develop severe hemorrhage and sometimes shock, resulting in more than 25,000 deaths annually (12). The 10.7-kb positive-stranded RNA genome of DENV encodes a polyprotein that is cleaved into 3 structural proteins, the envelope (E), the premembrane/membrane (prM/M), and the capsid (C), and 7 nonstructural (NS) proteins, NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. During replication, all DENV proteins and both positive-and negative-sense DENV RNAs are produced intracellularly, while only positive-sense RNA, the structural proteins, and NS1 are known to be secreted at high levels. Thus, based on current knowledge, NS proteins, with the exception of NS1, are restricted predominantly to cells in which DENV replicates.The cellular tropism of DENV has been investigated in humans (2, 5, 6, 8, 13, 15, 16, 25, 29) and mice (3, 9, 20, 38). In human studies, DENV antigen has been reported in the skin, liver, brain, kidney, spleen, lymph nodes, lungs, stomach, and intestines (2,5,6,8,13,15,16,25,29). These studies have mainly relied upon detection of secreted DENV antigens, which may actually localize elsewhere, complicating the interpretation of results. Recently two studies detected DENV NS antigen in the lymph nodes, spleen, liver, and ...

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Section: Discussionmentioning

confidence: 99%

Trafficking and Replication Patterns Reveal Splenic Macrophages as Major Targets of Dengue Virus in Mice

Prestwood

May

Plummer

et al. 2012

J Virol

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“…However, the characteristic induction of regulatory cytokines (TGF‐β, IL‐10) and IDO by apoptotic cells was shown to be abolished in STING‐deficient mice and proinflammatory IL‐6 expression was induced instead, revealing that cytosolic DNA sensing to activate STING is required for tolerogenic responses to dying cells . Similarly, microbial DNA sensing via STING in splenic or intestinal phagocytes that scavenge blood‐borne (such as Streptococcus ) or mucosal microbes to prevent sepsis or colitis may reinforce tolerance to protect tissues from immune‐mediated damage .…”

Section: Biologic Significance Of Dna‐induced Regulation: Good News Amentioning

confidence: 99%

Cytosolic DNA sensing via the stimulator of interferon genes adaptor: Yin and Yang of immune responses to DNA

et al. 2014

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Summary DNA is immunogenic and many cells express cytosolic DNA sensors that activate the Stimulator of Interferon Genes (STING) adaptor to trigger interferon type I (IFN-β) release, a potent immune activator. DNA sensing to induce IFN-β triggers host immunity to pathogens but constitutive DNA sensing can induce sustained IFN-β release which incites autoimmunity. Here we focus on cytosolic DNA sensing via the STING/IFN-β pathway which regulates immune responses. Recent studies reveal that cytosolic DNA sensing via the STING/IFN-β pathway induces indoleamine 2,3 dioxygenase (IDO), which catabolizes tryptophan to suppress effector and helper T-cell responses and activate Foxp3-lineage CD4+ regulatory T (Treg) cells. During homeostasis, and in some inflammatory settings, specialized innate immune cells in the spleen and lymph nodes may ingest and sense cytosolic DNA to reinforce tolerance that prevents autoimmunity. However, malignancies and pathogens may exploit DNA-induced regulatory responses to suppress natural and vaccine-induced immunity to malignant and infected cells. In this review we discuss the biologic significance of regulatory responses to DNA and novel approaches to exploit DNA-induced responses immune for therapeutic benefit. The ability of DNA to drive tolerogenic or immunogenic responses highlights the need to evaluate immune responses to DNA in physiologic settings relevant to disease progression or therapy.

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“…The MZ contains marginal zone macrophages, which are highly phagocytic, but represent a small fraction of the total macrophage/monocyte population in the spleen (27). The F4/80+ RP macrophage population can also phagocytose blood-borne microbes, particulate matter and aged erythrocytes, and are known to produce cytokines, including IL-1β, IL-6, IL-10, IL-12 and TGFβ (26, 28, 29). Exposure to the SDR stressor is known to increase monocyte levels, particularly CD11b + Ly6C hi monocytes, in the blood and in the spleen (10, 15, 18, 23).…”

Section: Introductionmentioning

confidence: 99%

Exposure to a Social Stressor Induces Translocation of Commensal Lactobacilli to the Spleen and Priming of the Innate Immune System

Lafuse

Gearinger

Fisher

et al. 2017

The Journal of Immunology

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Studies have shown that exposure to psychological stressors leads to inflammation throughout the body. This has been widely studied using social disruption stress (SDR), a social stressor, which involves repeated social defeat in subordinate mice. Exposure to SDR increases serum cytokine levels, results in accumulation of spleen CD11b+ myeloid cells, and primes macrophages for increased cytokine and microbicidal activity. Our previous studies showed that intestinal microbes are necessary for SDR-enhancement of innate immunity. Here, we show that SDR increases spleen CD11b+Ly6CintermLy6G+ neutrophil and CD11b+Ly6ChiLy6G− monocyte numbers compared to control mice. Further, we found that neutrophils and monocytes from stressor-exposed mice expressed higher levels of IL-1β mRNA. To determine whether bacterial translocation may contribute to these effects, bacterial 16S rRNA was quantified using qRT-PCR with bacterial group-specific primers. Exposure to the SDR stressor specifically increased Lactobacillus RNA in the spleen, which localized in spleen monocytes. The increased spleen levels of Lactobacillus 16S rRNA in SDR mice positively correlated with increased levels of IL-1β and IL-23 mRNA. Our findings indicate that during stressor exposure, Lactobacillus spp. can translocate to the spleen and prime the innate immune system for enhanced reactivity.

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SIGNR1-Negative Red Pulp Macrophages Protect against Acute Streptococcal Sepsis after Leishmania donovani-Induced Loss of Marginal Zone Macrophages

Cited by 30 publications

References 38 publications

Trafficking and Replication Patterns Reveal Splenic Macrophages as Major Targets of Dengue Virus in Mice

Trafficking and Replication Patterns Reveal Splenic Macrophages as Major Targets of Dengue Virus in Mice

Cytosolic DNA sensing via the stimulator of interferon genes adaptor: Yin and Yang of immune responses to DNA

Exposure to a Social Stressor Induces Translocation of Commensal Lactobacilli to the Spleen and Priming of the Innate Immune System

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