Interleukin-4 receptor alpha is still required after Th2 polarization for the maintenance and the recall of protective immunity to Nematode infection

Nono, Justin Komguep; Ndlovu, Hlumani; Aziz, Nada Abdel; Mpotje, Thabo; Hlaka, Lerato; Brombacher, Frank

doi:10.1371/journal.pntd.0005675

Cited by 10 publications

(13 citation statements)

References 34 publications

(61 reference statements)

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“…Infections with parasitic worms induce a T helper type 2 (Th2) immune response that is important for controlling parasite burdens during primary infection and for immunity to subsequent secondary infections [1–4]. Additionally, Th2 immune responses have evolved to rapidly repair tissue damage caused by parasitic worms, and to restore tissue integrity and homeostasis following parasite killing [5–7].…”

Section: Introductionmentioning

confidence: 99%

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

Batugedara

Jiang

Chen

et al. 2018

Journal of Leukocyte Biology

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Resistin-like molecule α (RELMα) is a highly secreted protein in type 2 (Th2) cytokine-induced inflammation including helminth infection and allergy. In infection with Nippostrongylus brasiliensis (Nb), RELMα dampens Th2 inflammatory responses. RELMα is expressed by immune cells, and by epithelial cells (EC); however, the functional impact of immune versus EC-derived RELMα is unknown. We generated bone marrow (BM) chimeras that were RELMα deficient (RELMα ) in BM or non BM cells and infected them with Nb. Non BM RELMα chimeras had comparable inflammatory responses and parasite burdens to RELMα mice. In contrast, both RELMα and BM RELMα mice exhibited increased Nb-induced lung and intestinal inflammation, correlated with elevated Th2 cytokines and Nb killing. CD11c lung macrophages were the dominant BM-derived source of RELMα and can mediate Nb killing. Therefore, we employed a macrophage-worm co-culture system to investigate whether RELMα regulates macrophage-mediated Nb killing. Compared to RELMα macrophages, RELMα macrophages exhibited increased binding to Nb and functionally impaired Nb development. Supplementation with recombinant RELMα partially reversed this phenotype. Gene expression analysis revealed that RELMα decreased cell adhesion and Fc receptor signaling pathways, which are associated with macrophage-mediated helminth killing. Collectively, these studies demonstrate that BM-derived RELMα is necessary and sufficient to dampen Nb immune responses, and identify that one mechanism of action of RELMα is through inhibiting macrophage recruitment and interaction with Nb. Our findings suggest that RELMα acts as an immune brake that provides mutually beneficial effects for the host and parasite by limiting tissue damage and delaying parasite expulsion.

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Section: Introductionmentioning

confidence: 99%

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

Batugedara

Jiang

Chen

et al. 2018

Journal of Leukocyte Biology

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“…Earlier studies aimed at elucidating the immunological factors driving host protective immunity to schistosomiasis took advantage of constitutive gene-deficient mouse models. These studies demonstrated that T and B cells (17–21) and Th2 effector molecules (IL-4, IL-13, IL-10, IL-4Rα, STAT-6) are crucial for conferring host protective immunity to infection (22–31). In our laboratory, we have looked in more detail at the cell-specific requirements of IL-4Rα in driving host survival during S. mansoni infection.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-4 Receptor Alpha Expressing B Cells Are Essential to Down-Modulate Host Granulomatous Inflammation During Schistosomasis

et al. 2018

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Schistosomiasis (bilharzia) is a parasitic helminth disease that can cause severe inflammatory pathology leading to organ damage in humans. Failure of the host to regulate egg-driven granulomatous inflammation causes host morbidity during chronic infection with Schistosoma mansoni. Although the importance of B cells in regulating pathology during chronic infection has been well defined, the specific contribution of IL-4Rα-expressing B cells is still unknown. To address this, we examined B cell-specific IL-4Rα-deficient (mb1creIL-4Rα−/lox) mice in three experimental models of schistosomiasis: high-dose (100 cercariae), low dose (30 cercariae), and a synchronous egg challenge. In the high dose model, we found that mice deficient in IL-4Rα-expressing B cells were more susceptible to acute schistosomiasis than B cell-deficient (μMT) mice, succumbing to infection at the acute stage whereas μMT mice survived until the chronic stage. An S. mansoni egg challenge model demonstrated that deleting IL-4Rα expression specifically on B cells resulted in increased lung granulomatous pathology, suggesting a role for this B cell subset in controlling granulomatous pathology. In agreement with this, a low dose model of schistosomiasis—which mimics the course of clinical chronic disease—demonstrated that depleting IL-4Rα-expressing B cells in mb1creIL-4Rα−/lox mice considerably impaired the host ability to down-modulate granulomatous inflammation in the liver and gut during chronic schistosomiasis. Taken together, our findings indicate that within the B cell compartment, IL-4Rα-expressing B cells in particular down-modulate the deleterious egg-driven tissue granulomatous inflammation to enable host survival during schistosomiasis in mice.

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“…The immune response to schistosomiasis, similarly to that against other tissue-dwelling helminth infections [ 4 – 6 ], is highly polarized as it progresses, going from i) an early Th1 response to ii) a powerful Th2 response that culminates as the adult parasite-released eggs are trapped in the host tissues [ 2 , 3 ] and finally iii) a chronic regulatory phase with a minimized but still dominant Th2 response [ 3 , 7 , 8 ] with a more clinically relevant tissue fibroproliferative pathology. Our current understanding of schistosomiasis pathology heavily relies on the use of experimental murine models [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Host regulation of liver fibroproliferative pathology during experimental schistosomiasis via interleukin-4 receptor alpha

et al. 2017

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Interleukin-4 receptor (IL-4Rα) is critical for the initiation of type-2 immune responses and implicated in the pathogenesis of experimental schistosomiasis. IL-4Rα mediated type-2 responses are critical for the control of pathology during acute schistosomiasis. However, type-2 responses tightly associate with fibrogranulomatous inflammation that drives host pathology during chronic schistosomiasis. To address such controversy on the role of IL-4Rα, we generated a novel inducible IL-4Rα-deficient mouse model that allows for temporal knockdown of il-4rα gene after oral administration of Tamoxifen. Interrupting IL-4Rα mediated signaling during the acute phase impaired the development of protective type-2 immune responses, leading to rapid weight loss and premature death, confirming a protective role of IL-4Rα during acute schistosomiasis. Conversely, IL-4Rα removal at the chronic phase of schistosomiasis ameliorated the pathological fibro-granulomatous pathology and reversed liver scarification without affecting the host fitness. This amelioration of the morbidity was accompanied by a reduced Th2 response and increased frequencies of FoxP3+ Tregs and CD1dhiCD5+ Bregs. Collectively, these data demonstrate that IL-4Rα mediated signaling has two opposing functions during experimental schistosomiasis depending on the stage of advancement of the disease and indicate that interrupting IL-4Rα mediated signaling is a viable therapeutic strategy to ameliorate liver fibroproliferative pathology in diseases like chronic schistosomiasis.

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Interleukin-4 receptor alpha is still required after Th2 polarization for the maintenance and the recall of protective immunity to Nematode infection

Cited by 10 publications

References 34 publications

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

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

Interleukin-4 Receptor Alpha Expressing B Cells Are Essential to Down-Modulate Host Granulomatous Inflammation During Schistosomasis

Host regulation of liver fibroproliferative pathology during experimental schistosomiasis via interleukin-4 receptor alpha

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