RELMα-expressing macrophages protect against fatal lung damage and reduce parasite burden during helminth infection

Krljanac, Branislav; Schubart, Christoph; Naumann, Ronald; Wirtz, Stefan; Culemann, Stephan; Krönke, Gerhard; Voehringer, David

doi:10.1126/sciimmunol.aau3814

Cited by 49 publications

(55 citation statements)

References 47 publications

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“…In the absence of IL-13, CD45 -EpCAM + epithelial cells had significantly impaired expression of RELM- as early as D2pi and was still muted by D6pi when compared to WT controls ( Figure 5D). Consistent with previous findings (36,37), epithelial cells were the major source of RELM- at these time points whilst other cellular sources such as alveolar macrophages, neutrophils, and eosinophils, were relatively unchanged in the absence of IL-13 following infection (data not shown). As a complementary experiment, equimolar amounts of systemic IL-4 and IL-13 were each delivered by intraperitoneal injection into WT mice and 18 h later epithelial RELM- expression was measured in the lungs.…”

Section: Il-13 Is Required For Induction Of Epithelial Cell-derived Rsupporting

confidence: 92%

IL-13 deficiency exacerbates lung damage and impairs epithelial-derived type 2 molecules during nematode infection

Chenery

Rosini

Parkinson

et al. 2020

Preprint

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IL-13 plays a key role during protective type 2 immune responses at mucosal sites, such as during infection with nematodes. However, dysregulation of IL-13 can also contribute to the pathogenesis of atopic and fibrotic diseases such as allergic asthma. Matrix remodelling is an important component of repair processes in the lung but also a hallmark of chronic conditions involving fibrosis. Hence, understanding the role of IL-13 in tissue remodelling has important clinical implications. Since IL-13 shares receptors and signalling pathways with IL-4, disentangling the relative contributions of these type 2 cytokines has been challenging. Additionally, little is known about the singular role of IL-13 following acute tissue injury. In this study, we used Nippostrongylus brasiliensis infection as a model of acute lung tissue damage comparing responses between WT and IL-13-deficient mice, in which IL-4 signalling is intact. Importantly, we found that IL-13 played a critical role in limiting tissue injury and haemorrhaging in the lung following infection. Through proteomic and transcriptomic profiling, we identified IL-13-dependent changes in matrix and associated regulators. We further showed that IL-13 is required for the induction of epithelial-derived type 2 effector molecules such as RELM-α and surfactant protein D. Pathway analyses predicted that IL-13 was heavily involved in the induction of cellular stress responses and regulation of lung epithelial cell differentiation by suppression of Foxa2 pathways. Thus, we propose that IL-13 has tissue-protective functions during lung injury and regulates epithelial cell responses during type 2 immunity in this acute setting.

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Section: Il-13 Is Required For Induction Of Epithelial Cell-derived Rsupporting

confidence: 92%

IL-13 deficiency exacerbates lung damage and impairs epithelial-derived type 2 molecules during nematode infection

Chenery

Rosini

Parkinson

et al. 2020

Preprint

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“…Here we show that RELMα was expressed in some CD68+ macrophages as expected (presumably AA/M2 macrophages) but in addition CD68-cells in the parenchyma (Figure 2). Others have shown that RELMα can be expressed by alveolar type II epithelial cells using RELMα promoter reporter mice [40]. Thus, alveolar type II epithelial cells may also be responsive to OSM with RELMα expression (we have published that these cells express IL-33 in response to OSM in vitro and in vitro).…”

Section: Discussionmentioning

confidence: 65%

RELMα Is Induced in Airway Epithelial Cells by Oncostatin M without Requirement of STAT6 or IL-6 in Mouse Lungs In Vivo

Yip

Lao

et al. 2020

Cells

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Resistin-like molecule alpha (RELMα) and YM-1 are secreted proteins implicated in murine models of alternatively activated macrophage (AA/M2) accumulation and Th2-skewed inflammation. Since the gp130 cytokine Oncostatin M (OSM) induces a Th2-like cytokine and AA/M2 skewed inflammation in mouse lung, we here investigated regulation of RELMα and YM-1. Transient pulmonary overexpression of OSM by Adenovirus vector (AdOSM) markedly induced RELMα and YM-1 protein expression in total lung. In situ hybridization showed that RELMα mRNA was highly induced in airway epithelial cells (AEC) and was co-expressed with CD68 mRNA in some but not all CD68+ cells in parenchyma. IL-6 overexpression (a comparator gp130 cytokine) induced RELMα, but at significantly lower levels. IL-6 (assessing IL-6−/− mice) was not required, nor was STAT6 (IL-4/13 canonical signalling) for AdOSM-induction of RELMα in AEC. AEC responded directly to OSM in vitro as assessed by pSTAT3 activation. RELMα-deficient mice showed similar inflammatory cell infiltration and cytokine responses to wt in response to AdOSM, but showed less accumulation of CD206+ AA/M2 macrophages, reduced induction of extracellular matrix gene mRNAs for COL1A1, COL3A1, MMP13, and TIMP1, and reduced parenchymal alpha smooth muscle actin. Thus, RELMα is regulated by OSM in AEC and contributes to extracellular matrix remodelling in mouse lung.

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“…Most sources are consistent with these explanations, but nevertheless, there have also been reports stating that for example the AAM response is unsafe for helminths and instead, the parasite seeks to inhibit AAM production and accepts the production of classically activated macrophages (71). In fact, it has been shown that AAMs protect mice from secondary infections with H. bakeri (72) and N. brasiliensis (73). Nonetheless, more research is required to understand how AAMs regulate anti-helminth immunity and restore tissue integrity.…”

Section: Discussionmentioning

confidence: 98%

Immunomodulation and Immune Escape Strategies of Gastrointestinal Helminths and Schistosomes

Wiedemann

Voehringer

2020

Front. Immunol.

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Parasitic worms (helminths) developed various immunoregulatory mechanisms to counteract the immune system of their host. The increasing identification and characterization of helminth-derived factors with strong immune modulatory activity provides novel insights into immune escape strategies of helminths. Such factors might be good targets to enhance anti-helminthic immune responses. In addition, immunosuppressive helminth-derived factors could be useful to develop new therapeutic strategies for treatment of chronic inflammatory conditions. This review will take an in depth look at the effects of immunomodulatory molecules produced by different helminths with a focus on schistosomes and mouse models of hookworm infections.

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RELMα-expressing macrophages protect against fatal lung damage and reduce parasite burden during helminth infection

Cited by 49 publications

References 47 publications

IL-13 deficiency exacerbates lung damage and impairs epithelial-derived type 2 molecules during nematode infection

IL-13 deficiency exacerbates lung damage and impairs epithelial-derived type 2 molecules during nematode infection

RELMα Is Induced in Airway Epithelial Cells by Oncostatin M without Requirement of STAT6 or IL-6 in Mouse Lungs In Vivo

Immunomodulation and Immune Escape Strategies of Gastrointestinal Helminths and Schistosomes

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