Sustained IL-4 exposure leads to a novel pathway for hemophagocytosis, inflammation, and tissue macrophage accumulation

Milner, Joshua D.; Orekov, Tatyana; Ward, Jerrold M.; Cheng, Lily; Torres-Vélez, Fernando J.; Junttila, Ilkka; Sun, Guangping; Buller, Mark; Morris, Suzanne C.; Finkelman, Fred D.; Paul, William E.

doi:10.1182/blood-2009-11-255174

Cited by 103 publications

(88 citation statements)

References 22 publications

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“…This so-called cytokine storm could pathogenically contribute to tissue damage and progressive systemic organ failure. Improper intracellular trafficking and impaired apoptosis have also been implicated [1,20,21]. The strikingly inflammatory state promoted by hypercytokinemia could explain the beneficial role of high dose steroids that we observed.…”

Section: Comorbidities/ Co-morbid Infectionssupporting

confidence: 52%

Influenza-Associated Hemophagocytic Syndrome in Adults: Case Report and Review

Trujillo¹,

Lalueza²,

Blanco³

et al. 2018

J Antivir Antiretrovir

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Section: Comorbidities/ Co-morbid Infectionssupporting

confidence: 52%

Influenza-Associated Hemophagocytic Syndrome in Adults: Case Report and Review

Trujillo¹,

Lalueza²,

Blanco³

et al. 2018

J Antivir Antiretrovir

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“…7), were observed in serum and were highest during the acute stage of infection. IL-4 was high early in infection and further increased by 3 weeks postinfection, consistent with a subacute, alternative activation state in select macrophage populations (41,42), including hemophagocytes (28). Thus, Salmonella-infected mice have a particularly strong proinflammatory response at 1 week postinfection that declines but remains significantly higher than that of control mice over the subsequent 3 weeks.…”

Section: Quantification Of Reduced Splenic Iron In Infected Micementioning

confidence: 71%

“…3) and in our prior studies (7,8,10,28). Sustained exogenous delivery of cytokines (IFN-␥ or IL-4) or a TLR9 agonist (CpG) promotes tissue hemophagocytosis and the development of anemia (42,51,52). Additionally, sustained increases in serum TNF-␣ contribute to erythrocyte damage (53) and subsequent erythrophagocytosis (54).…”

Section: Discussionmentioning

confidence: 89%

Increased Ferroportin-1 Expression and Rapid Splenic Iron Loss Occur with Anemia Caused by Salmonella enterica Serovar Typhimurium Infection in Mice

et al. 2015

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e The Gram-negative intracellular bacterium Salmonella enterica serovar Typhimurium causes persistent systemic inflammatory disease in immunocompetent mice. Following oral inoculation with S. Typhimurium, mice develop a hematopathological syndrome akin to typhoid fever with splenomegaly, microcytic anemia, extramedullary erythropoiesis, and increased hemophagocytic macrophages in the bone marrow, liver, and spleen. Additionally, there is marked loss of iron from the spleen, an unanticipated result, given the iron sequestration reported in anemia of inflammatory disease. To establish why tissue iron does not accumulate, we evaluated multiple measures of pathology for 4 weeks following oral infection in mice. We demonstrate a quantitative decrease in splenic iron following infection despite increased numbers of splenic phagocytes. Infected mice have increased duodenal expression of the iron exporter ferroportin-1, consistent with increased uptake of dietary iron. Liver and splenic macrophages also express high levels of ferroportin-1. These observations indicate that splenic and hepatic macrophages export iron during S. Typhimurium infection, in contrast to macrophage iron sequestration observed in anemia of inflammatory disease. Tissue macrophage export of iron occurs concurrent with high serum concentrations of interferon gamma (IFN-␥) and interleukin 12 (IL-12). In individual mice, high concentrations of both proinflammatory (tumor necrosis factor alpha [TNF-␣])and anti-inflammatory (IL-10) cytokines in serum correlate with increased tissue bacterial loads throughout 4 weeks of infection. These in vivo observations are consistent with previous cell culture studies and suggest that the relocation of iron from tissue macrophages during infection may contribute to anemia and also to host survival of acute S. Typhimurium infection.T yphoid fever is acquired upon oral ingestion of food or water contaminated with Salmonella enterica serovar Typhi or Paratyphi and remains a serious threat to public health, especially in developing countries (1). Human typhoid fever causes a broad range of clinical signs, including splenomegaly, neuropathy, and hematopathology, such as cytopenias (2), that have been modeled in laboratory mice infected with Salmonella enterica serovar Typhimurium (3). Inbred mouse strains with differing genetic backgrounds are characterized as either sensitive or resistant to S. Typhimurium. Sensitivity to the intracellular bacterial infection is caused by genetic deficiencies in the innate or adaptive immune system (4, 5). For instance, mice lacking the cation transporter Nramp1 (Slc11a1), a regulator of cellular iron metabolism, are extremely sensitive to infection. Nramp1 ϩ mice are considered resistant to S. Typhimurium, because infection is generally nonfatal (6-8). Resistant mice infected by natural oral inoculation develop systemic infection with an acute hematopathological syndrome similar to that of humans with typhoid fever, including fever, anemia, inflammatory disease characterized by periph...

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“…This produces an exaggerated inflammatory response and hypersecretion of cytokines in what is known as a "cytokine storm" [16]. This manifests in the main clinical and laboratory abnormalities of HLH and eventually results in tissue damage and organ failure.…”

Section: Discussionmentioning

confidence: 99%

Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis

2015

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Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by the activation of the mononuclear phagocytic system. The diagnosis of HLH in adults is challenging not only because the majority of the reported data are from pediatric patients, but also because HLH occurs in many disease entities. This study reports the clinical and laboratory findings and prognostic factors of adult HLH in a large cohort managed at a single medical center from 2003 to 2014. Seventy-three patients met the HLH-2004 diagnostic criteria. The median age was 51 years (range, 18-82 years); 41 (56.2%) were male. Patients manifested fever, cytopenias, and elevated ferritin in >85% of cases. Likely causes of HLH were as follows: 30 (41.1%) infections, 21 (28.8%) malignancies, 5 (6.8%) attributed to autoimmune disorders, 1 (1.4%) primary immunodeficiency, 2 (2.7%) post solid organ transplantation, and 13 (17.8%) idiopathic. The median overall survival was 7.67 months. Patients with malignancy-associated HLH had a markedly worse survival compared with patients with non-malignancy-associated HLH (median overall survival 1.13 vs. 46.53 months, respectively; P < 0.0001). In a multivariable analysis, malignancy (hazard ratio 5 12.22; 95% CI: 2.53-59.02; P 5 0.002) correlated with poor survival. Ferritin >50,000 mg/L correlated with 30-day mortality. Survival after a diagnosis of HLH is dismal, especially among those with malignancy-associated HLH. The development of a registry for adults with HLH would improve our understanding of this syndrome, validate diagnostic criteria, and help develop effective treatment strategies.

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Sustained IL-4 exposure leads to a novel pathway for hemophagocytosis, inflammation, and tissue macrophage accumulation

Cited by 103 publications

References 22 publications

Influenza-Associated Hemophagocytic Syndrome in Adults: Case Report and Review

Influenza-Associated Hemophagocytic Syndrome in Adults: Case Report and Review

Increased Ferroportin-1 Expression and Rapid Splenic Iron Loss Occur with Anemia Caused by Salmonella enterica Serovar Typhimurium Infection in Mice

Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis

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