Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology.

By D. Herbert, C. Hölscher, M. Mohrs, B. Arendse, Anita Schwegmann, M. Radwanska, Mosiuoa Leeto, R. Kirsch, P. Hall, H. Mossmann and 3 more. Immunity, 2004

779 citations recorded by the source corpus.

Macrophage/neutrophil-specific IL-4 receptor alpha-deficient mice (LysM(Cre)IL-4Ralpha(-/flox)) were generated to understand the role of IL-4/IL-13 responsive myeloid cells during Type 2 immune responses. LysM(Cre)IL-4Ralpha(-/flox) mice developed protective immunity against Nippostrongylus brasiliensis accompanied by T(H)2 development and goblet cell hyperplasia. In contrast, LysM(Cre)IL-4Ralpha(-/flox) mice were extremely susceptible to Schistosoma mansoni infection with 100% mortality during acute infection. Mortality was not dependent on neutrophils and occurred in the presence of T(H)2/Type 2 responses, granuloma formation, and egg-induced fibrosis. Death was associated with increased T(H)1 cytokines, hepatic and intestinal histopathology, increased NOS-2 activity, impaired egg expulsion, and sepsis. IL-10 was not able to compensate for the absence of IL-4/IL-13-activated alternative macrophages. Together, this shows that alternative macrophages are essential during schistosomiasis for protection against organ injury through downregulation of egg-induced inflammation.

Subfields: Immunology, Parasitology, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/79a150e39c1c876ed75b83a838867b24ea56906e

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In Immunology

1. TA Wynn
2. R. Locksley
3. P. Murray
4. S. Gordon
5. A. Chawla
6. A. Mantovani
7. F. Martínez
8. T. Lawrence

In Parasitology

1. TA Wynn
2. R. Locksley
3. J. Allen
4. S. V. Van Dyken
5. A. Mantovani

In Public Health, Environmental and Occupational Health

1. I. McInnes

Citations in the corpus

• Arginase: an emerging key player in the mammalian immune system (2009, background): “absence of alternatively activated macrophages) during acute infection with Schistosoma mansoni (Herbert et al., 2004).”
• INTERLEUKIN-4- AND INTERLEUKIN-13-MEDIATED ALTERNATIVELY ACTIVATED MACROPHAGES: ROLES IN HOMEOSTASIS AND DISEASE (2013, neutral): “In contrast to global IL-4Rα deficiency, however, myeloid-restricted IL-4Rα-deficient mice retained robust eosinophilic granuloma formation and fibrosis, along with antigen-specific Th2 responses (155).”
• Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. (2008, background): “While these and other studies have delineated the pathogenic activities of inflammatory Kupffer cells, resident hepatic macrophages display tremendous plasticity in their activation programs, ranging from the proinflammatory classical state to the anti-inflammatory alternative state (Gordon, 2003; H”
• Transcriptional regulation of macrophage polarization: enabling diversity with identity (2011, background): “Mice with a myeloid cell-specific knockout of IL-4 receptor-α ( Il4ra ) were found to lack M2 macrophage development in mouse models of helminth infection and in T H 2 cell-mediated inflammation, where IL-4 has a major rol”
• Local macrophage proliferation, rather than recruitment from the blood, is a signature of Th2 inflammation (2011, positive): “C57BL/6 Rag1, C57BL/6 Il4 and BALB/c Il4ra were produced and obtained as described previously (18, 32).”
• Macrophage plasticity and polarization: in vivo veritas. (2012, neutral): “mansoni, but has no discernible effect on Nippostrongylus infection (70).”
• Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis (2011, background): “To determine whether the observed defects in cold-induced thermogenesis were a direct consequence of the loss of alternatively activated macrophages, we disrupted IL-4/IL-13 signalling in myeloid cells by breeding conditional Il4ra LoxP/LoxP with Lysm Cre mic”
• Macrophages: Master Regulators of Inflammation and Fibrosis (2010, background): “Therefore, at least in the context of schistosomiasis, AAMw are not strictly required for the development of hepatic fibrosis or granuloma formation, but instead avert acute morbidity and mortality by down-regulating proinflammatory cytokine expression in the intestine.(151) The specific contributio”
• Alternative activation of macrophages: mechanism and functions. (2010, background): “Function of Signature Markers in AAM In the case of enzyme markers such as Arg1, there has been extensive investigation of its possible role in alternative versus classical activation (De’Broski et al., 2010; El Kasmi et al., 2008; Herbert et al., 2004; Pesce et al., 2009a).”
• Mechanisms of fibrosis: therapeutic translation for fibrotic disease (2012, positive): “…mice, in which Cre-mediated recombination results in deletion of the IL-4R α chain in the myeloid cell lineage, including in M2 cells, have demonstrated that M2 macrophages are not required for the development of T H 2 responses or liver fibrosis following infection with Schistosoma mansoni 44 .”
• Arginase-1–Expressing Macrophages Suppress Th2 Cytokine–Driven Inflammation and Fibrosis (2009, background): “Together, these observations suggest that the cause of death in the Arg1;LysMcre mice is distinct from the mechanism observed in Il4 and Il4ra;LysMcre mice [23,28], which was attributed to acute Th1 cytokine and endotoxin-mediated toxicity.”
• IL-33 Amplifies the Polarization of Alternatively Activated Macrophages That Contribute to Airway Inflammation1 (2009, background): “Given the well-established involvement of IL-4, IL-13, and IL4R (shared by IL-4 and IL-13) in AAM differentiation (3, 30, 31), we evaluated the contribution of these factors to IL-33-amplified AAM development.”