IL-4Rα-expressing CD11c+ cells contribute to driving optimal cellular responses during <i>Schistosoma mansoni</i> infection in mice

Ndlovu, Hlumani; Nono, Justin Komguep; Nieuwenhuizen, Natalie E.; Brombacher, Frank

doi:10.1002/jlb.ma0318-115r

Cited by 6 publications

(4 citation statements)

References 39 publications

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“…Namely, IL-4 receptor expression on alternatively activated macrophages and myeloid cells in general appears to drive specific aspects of S. mansoni pathology (44,45). IL-4 receptor is expressed by diverse cell types such as CD4 ϩ and CD4 -T cells (46,47), smooth muscle cells (48), B cells (49), FoxP3 ϩ regulatory T cells (50), and CD11c ϩ cells (51). This corpus of research suggested to us that urothelial IL-4 receptor could be important in the bladder pathogenesis of urogenital schistosomiasis.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-4 Signaling Plays a Major Role in Urogenital Schistosomiasis-Associated Bladder Pathogenesis

Mbanefo

et al. 2020

Infect Immun

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Interleukin-4 (IL-4) is crucial in many helminth infections, but its role in urogenital schistosomiasis, infection with Schistosoma haematobium worms, remains poorly understood due to a historical lack of animal models. The bladder pathology of urogenital schistosomiasis is caused by immune responses to eggs deposited in the bladder wall. A range of pathology occurs, including urothelial hyperplasia and cancer, but associated mechanisms and links to IL-4 are largely unknown. We modeled urogenital schistosomiasis by injecting the bladder walls of IL-4 receptor-alpha knockout (Il4ra−/−) and wild-type mice with S. haematobium eggs. Readouts included bladder histology and ex vivo assessments of urothelial proliferation, cell cycle, and ploidy status. We also quantified the effects of exogenous IL-4 on urothelial cell proliferation in vitro, including cell cycle status and phosphorylation patterns of major downstream regulators in the IL-4 signaling pathway. There was a significant decrease in the intensity of granulomatous responses to bladder-wall-injected S. haematobium eggs in Il4ra−/− versus wild-type mice. S. haematobium egg injection triggered significant urothelial proliferation, including evidence of urothelial hyper-diploidy and cell cycle skewing in wild-type but not Il4ra−/− mice. Urothelial exposure to IL-4 in vitro led to cell cycle polarization and increased phosphorylation of AKT. Our results show that IL-4 signaling is required for key pathogenic features of urogenital schistosomiasis and that particular aspects of this signaling pathway may exert these effects directly on the urothelium. These findings point to potential mechanisms by which urogenital schistosomiasis promotes bladder carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Interleukin-4 Signaling Plays a Major Role in Urogenital Schistosomiasis-Associated Bladder Pathogenesis

Mbanefo

et al. 2020

Infect Immun

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“…Namely, IL-4 receptor expression on alternatively activated macrophages and myeloid cells in general appears to drive specific aspects of S. mansoni pathology [38, 39]. IL-4 receptor expression by diverse cell types such as CD4+ and CD4-T cells [40, 41], smooth muscle cells [42], B cells [43], FoxP3+ regulatory T cells [44], and CD11c + cells [45]. This corpus of research suggested to us that urothelial IL-4 receptor could be important in the bladder pathogenesis of urogenital schistosomiasis.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-4 signaling plays a major role in urogenital schistosomiasis-associated bladder pathogenesis

Mbanefo

et al. 2019

Preprint

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19IL-4 is crucial in many helminth infections, but its role in urogenital schistosomiasis, infection with 20 Schistosoma haematobium worms, remains poorly understood due to a historical lack of animal models. 21The bladder pathology of urogenital schistosomiasis is caused by immune responses to eggs deposited in 22 the bladder wall. A range of pathology occurs, including urothelial hyperplasia and cancer, but 23 associated mechanisms and links to IL-4 are largely unknown. We modeled urogenital schistosomiasis 24 by injecting the bladder walls of IL-4 receptor-alpha knockout(Il4ra -/-) and wild type mice with S. 25 haematobium eggs. Readouts included bladder histology and ex vivo assessments of urothelial 26 proliferation, cell cycle and ploidy status. We also quantified the effects of exogenous IL-4 on urothelial 27 cell proliferation in vitro, including cell cycle status and phosphorylation patterns of major downstream 28 regulators in the IL-4 signaling pathway. There was a significant decrease in the intensity of 29 granulomatous responses to bladder-wall injected S. haematobium eggs in Il4ra -/versus wild type mice. 30 S. haematobium egg injection triggered significant urothelial proliferation, including evidence of 31 urothelial hyperdiploidy and cell cycle skewing in wild type but not Il4ra -/mice. Urothelial exposure to 32 IL-4 in vitro led to cell cycle polarization and increased phosphorylation of AKT. Our results show IL-4 33 signaling is required for key pathogenic features of urogenital schistosomiasis, and that particular 34 aspects of this signaling pathway may exert these effects directly on the urothelium. These findings 35 point to potential mechanisms by which urogenital schistosomiasis promotes bladder carcinogenesis. 36 37 unfortunately sets the stage for the characteristic fibrotic response. For intestinal schistosomiasis, 48 hepatosplenomegaly and portal hypertension may result, or bladder cancer in the case of urogenital 49 schistosomiasis. 50The exact underlying mechanism by which schistosome eggs induce IL-4 production/release is still 51 uncertain [2]. The major sources of IL-4 have also been shown to include other sources beyond the Th2 52 cells themselves [14]. Parasite egg crude extract has been shown to stimulate enormous IL-4 release 53 from basophils [2, 15], mast cells and other non-T-cell, non-B-cell populations [16], which may indeed 54 represent constitutive sources of IL-4, apart from the Th2 cells. Other Fcε receptor negative non-55 lymphocyte sources of IL-4 have also been reported [17, 18]. The most abundant IL-4 inducing egg 56 antigen has since been identified and characterized from S. mansoni and S. haematobium [2, 15, 19, 20]. 57The interleuking-4 inducing principle from Schistosoma eggs (IPSE) binds to IgE on the surface of these 58 non-T-cell sources, inducing massive IL-4 release that subsequently drive type-2 response [2, 15, 19, 59 20]. 60Although the role of IL-4 in driving schistosomiasis-induced pathogenesis is widely studied for hepato-61 splenic schistosomi...

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“…Together with studies showing that the deletion of IL‐4Rα in DCs and monocytes impaired Th2 responses to the parasite Schistosoma mansoni [69], as well as the differentiation of Th2 cells and infiltration of eosinophils into the lung in a model of allergic airway inflammation induced by house dust mite [70], these observations suggest that IL‐13 skews DC function toward a Th2 stimulatory function, regardless of tissue location and of whether IL‐13 is produced at steady state or induced by cytokine signaling or antigen recognition.…”

Section: Specialization In Nonlymphoid Tissuementioning

confidence: 95%

IL‐13 in dermal type‐2 dendritic cell specialization: From function to therapeutic targeting

2022

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Skin functions as a barrier protecting the host against physical, thermal, chemical changes as well as microbial insults. The skin is populated by several immune cell types that are crucial to host defense and to maintain self-tolerance as well as equilibrium with beneficial microbiota. Conventional dendritic cells (cDCs) are antigen-presenting cells that patrol the skin and all other nonlymphoid tissues for self or foreign antigens, and then migrate to draining lymph nodes to initiate T-cell responses. This review article describes recent developments on skin cDC specialization, focusing on the role of IL-13, a cytokine essential to allergic immune responses that is also secreted at steady state by type-2 innate lymphoid cells in healthy skin, and is required for dermal cDC differentiation. Furthermore, we contextualize how different therapeutics that block IL-13 signaling and were recently approved for the treatment of atopic dermatitis might affect cDCs in human skin.

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IL-4Rα-expressing CD11c+ cells contribute to driving optimal cellular responses during Schistosoma mansoni infection in mice

Cited by 6 publications

References 39 publications

Interleukin-4 Signaling Plays a Major Role in Urogenital Schistosomiasis-Associated Bladder Pathogenesis

Interleukin-4 Signaling Plays a Major Role in Urogenital Schistosomiasis-Associated Bladder Pathogenesis

Interleukin-4 signaling plays a major role in urogenital schistosomiasis-associated bladder pathogenesis

IL‐13 in dermal type‐2 dendritic cell specialization: From function to therapeutic targeting

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