Interferon‐γ Mediates Anemia but Is Dispensable for Fulminant Toll‐like Receptor 9–Induced Macrophage Activation Syndrome and Hemophagocytosis in Mice. Issue 7 (2nd July 2013)

• Record Type: Journal Article
• Authors: Canna, Scott W.; Wrobel, Julia; Chu, Niansheng; Kreiger, Portia A.; Paessler, Michele; Behrens, Edward M.
• Is Part Of: Arthritis and rheumatism. Volume 65:Issue 7(2013:Jul.)
• Page Start: 1764
• Page End: 1775
• Publication Date: 2013-07-02
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; Arthritis -- Periodicals; Rheumatic Diseases -- Periodicals; Rhumatisme -- Périodiques; Arthrite -- Périodiques; 616.72
• DOI: 10.1002/art.37958
• Languages: English
• ISSNs: 0004-3591

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="art37958-sec-0001" sec-type="section"> <title>Objective</title> <p>Macrophage activation syndrome (MAS) is a devastating cytokine storm syndrome complicating many inflammatory diseases and characterized by fever, pancytopenia, and systemic inflammation. It is clinically similar to hemophagocytic lymphohistiocytosis (HLH), which is caused by viral infection of a host with impaired cellular cytotoxicity. Murine models of MAS and HLH illustrate that interferon‐γ (IFNγ) is the driving stimulus for hemophagocytosis and immunopathology. This study was undertaken to investigate the inflammatory contributors to a murine model of Toll‐like receptor 9 (TLR‐9)–induced fulminant MAS.</p> </sec> <sec id="art37958-sec-0002" sec-type="section"> <title>Methods</title> <p>Wild‐type, transgenic, and cytokine‐inhibited mice were treated with an IL‐10 receptor blocking antibody and a TLR‐9 agonist, and parameters of MAS were evaluated.</p> </sec> <sec id="art37958-sec-0003" sec-type="section"> <title>Results</title> <p>Fulminant MAS was characterized by dramatic elevations in IFNγ, IL‐12, and IL‐6 levels. Increased serum IFNγ levels were associated with enhanced IFNγ production within some hepatic cell populations but also with decreased numbers of IFNγ‐positive cells. Surprisingly, IFNγ‐knockout mice developed immunopathology and hemophagocytosis comparable to that seen in wild‐type mice. However, IFNγ‐knockout mice did not become anemic and had greater numbers of splenic erythroid precursors. IL‐12 neutralization phenocopied disease in IFNγ‐knockout mice. Interestingly, type I IFNs contributed to the severity of hypercytokinemia and weight loss, but their absence did not otherwise affect MAS manifestations.</p> </sec> <sec id="art37958-sec-0004" sec-type="section"> <title>Conclusion</title> <p>These data demonstrate that both fulminant MAS and hemophagocytosis can arise independently of IFNγ, IL‐12, or type I IFNs. They also suggest that IFNγ‐mediated dyserythropoiesis, not hemophagocytosis, is the dominant cause of anemia in fulminant TLR‐9–induced MAS. Thus, our data establish a novel mechanism for the acute anemia of inflammation, but suggest that a variety of triggers can result in hemophagocytic disease.</p> </sec> </abstract>