Hematopoietic cell-derived RELMα regulates hookworm immunity through effects on macrophages

Batugedara, Hashini Maneesha; Jiang, Li; Chen, Gang; Lu, Dihong; Patel, Jay J.; Jang, Jessica C.; Radecki, Kelly C.; Burr, Abigail; Lo, David; Dillman, Adler R.; Nair, Meera G.

doi:10.1002/jlb.4a0917-369rr

Cited by 21 publications

(22 citation statements)

References 75 publications

(135 reference statements)

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“…However, it remains to be seen how tightly linked Ym1’s functions are to its ability to induce RELMα. In addition, recent data suggest that macrophage-derived RELMα is critical for its regulatory function [64] and we have yet to establish whether the ability of Ym1 to induce RELMα is restricted to epithelial cells. Finally, the changes in Ym1 function over time may largely relate to its ability to bind ECM, the properties of which will change over the course of an immune response.…”

Section: Discussionmentioning

confidence: 99%

Ym1 induces RELMα and rescues IL-4Rα deficiency in lung repair during nematode infection

et al. 2018

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Ym1 and RELMα are established effector molecules closely synonymous with Th2-type inflammation and associated pathology. Here, we show that whilst largely dependent on IL-4Rα signaling during a type 2 response, Ym1 and RELMα also have IL-4Rα-independent expression patterns in the lung. Notably, we found that Ym1 has opposing effects on type 2 immunity during nematode infection depending on whether it is expressed at the time of innate or adaptive responses. During the lung migratory stage of Nippostrongylus brasiliensis, Ym1 promoted the subsequent reparative type 2 response but once that response was established, IL-4Rα-dependent Ym1 was important for limiting the magnitude of type 2 cytokine production from both CD4+ T cells and innate lymphoid cells in the lung. Importantly, our study demonstrates that delivery of Ym1 to IL-4Rα deficient animals drives RELMα production and overcomes lung repair deficits in mice deficient in type 2 immunity. Together, Ym1 and RELMα, exhibit time and dose-dependent interactions that determines the outcome of lung repair during nematode infection.

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Section: Discussionmentioning

confidence: 99%

Ym1 induces RELMα and rescues IL-4Rα deficiency in lung repair during nematode infection

et al. 2018

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“…RELMα activates the enzyme lysyl hydrolase 2 ( Plod2 ), which mediates optimal collagen cross‐linking . Additionally, macrophage‐derived RELMα was implicated in dampening lung inflammation and promoting tissue repair in a model of helminth infection‐induced lung injury with rodent hookworm Nippostrongylus brasiliensis . In this model, gene expression analysis of RELMα‐treated lung macrophages revealed that RELMα promoted expression of genes involved in extracellular matrix remodeling: matrix metalloproteinase 9 ( Mmp9 ), integrin beta 1 ( Itgb1 ) and junctional adhesion molecule A ( F11r ).…”

Section: Wound‐healing Macrophage Activation and Functionmentioning

confidence: 99%

Macrophages in wound healing: activation and plasticity

2019

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Macrophages are critically involved in wound healing, from dampening inflammation to clearing cell debris and coordinating tissue repair. Within the wound, the complexity of macrophage function is increasingly recognized, with adverse outcomes when macrophages are inappropriately activated, such as in fibrosis or chronic non‐healing wounds. Recent advances in in vivo and translational wound models, macrophage‐specific deletions and new technologies to distinguish macrophage subsets, have uncovered the vast spectrum of macrophage activation and effector functions. Here, we summarize the main players in wound‐healing macrophage activation and function, including cytokines, apoptotic cells, nucleotides and mechanical stimuli. We highlight recent studies demonstrating cooperation between these factors for optimal wound healing. Next, we describe recent technologies such as cell tracking and single‐cell RNA‐seq, which have uncovered remarkable plasticity and heterogeneity in blood‐derived or tissue‐resident macrophages and discuss the implications for wound healing. Lastly, we evaluate macrophage dysfunction in aberrant wound healing that occurs in aging, diabetes and fibrosis. A better understanding of the longevity and plasticity of wound‐healing macrophages, and identification of unique macrophage subsets or specific effector molecules in wound healing, would shed light on the therapeutic potential of manipulating macrophage function for optimal wound healing.

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“…Studies in pulmonary inflammation, hypertension and fibrosis, point to an inflammatory function for RELMa by promoting immune cell recruitment, fibroblast activation and proliferation associated with pathogenic fibrosis (20,21). On the other hand, in response to tissue migratory helminth parasites, RELMa critically prevents fatal lung tissue damage, granulomatous inflammation, and promotes tissue repair (22)(23)(24)(25)(26)(27)(28). Downstream regulatory mechanisms for RELMa include limiting CD4 + T cell polarization, promoting anti-inflammatory responses, and mediating collagen cross-linking associated with tissue healing (26,29,30).…”

Section: Introductionmentioning

confidence: 99%

Macrophage-Regulatory T Cell Interactions Promote Type 2 Immune Homeostasis Through Resistin-Like Molecule α

Kim

Lainez

et al. 2021

Front. Immunol.

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RELMα is a small, secreted protein expressed by type 2 cytokine-activated “M2” macrophages in helminth infection and allergy. At steady state and in response to type 2 cytokines, RELMα is highly expressed by peritoneal macrophages, however, its function in the serosal cavity is unclear. In this study, we generated RELMα TdTomato (Td) reporter/knockout (RαTd) mice and investigated RELMα function in IL-4 complex (IL-4c)-induced peritoneal inflammation. We first validated the RELMαTd/Td transgenic mice and showed that IL-4c injection led to the significant expansion of large peritoneal macrophages that expressed Td but not RELMα protein, while RELMα+/+ mice expressed RELMα and not Td. Functionally, RELMαTd/Td mice had increased IL-4 induced peritoneal macrophage responses and splenomegaly compared to RELMα+/+ mice. Gene expression analysis indicated that RELMαTd/Td peritoneal macrophages were more proliferative and activated than RELMα+/+ macrophages, with increased genes associated with T cell responses, growth factor and cytokine signaling, but decreased genes associated with differentiation and maintenance of myeloid cells. We tested the hypothesis that RαTd/Td macrophages drive aberrant T cell activation using peritoneal macrophage and T cell co-culture. There were no differences in CD4+ T cell effector responses when co-cultured with RELMα+/+ or RELMαTd/Td macrophages, however, RELMαTd/Td macrophages were impaired in their ability to sustain proliferation of FoxP3+ regulatory T cells (Treg). Supportive of the in vitro results, immunofluorescent staining of the spleens revealed significantly decreased FoxP3+ cells in the RELMαTd/Td spleens compared to RELMα+/+ spleens. Taken together, these studies identify a new RELMα regulatory pathway whereby RELMα-expressing macrophages directly sustain Treg proliferation to limit type 2 inflammatory responses.

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Hematopoietic cell-derived RELMα regulates hookworm immunity through effects on macrophages

Cited by 21 publications

References 75 publications

Ym1 induces RELMα and rescues IL-4Rα deficiency in lung repair during nematode infection

Ym1 induces RELMα and rescues IL-4Rα deficiency in lung repair during nematode infection

Macrophages in wound healing: activation and plasticity

Macrophage-Regulatory T Cell Interactions Promote Type 2 Immune Homeostasis Through Resistin-Like Molecule α

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