Investigating the role of IL-4/IL-13 and their receptors in ulcerative colitis

Ulcerative colitis (UC) is a heterogeneous inflammatory bowel disease (IBD) associated with chronic inflammation of the gastrointestinal tract. Characterized by genetic and immunological abnormalities, UC has overly aggressive T-cell responses to commensal bacteria eventually leading to disease pathology. UC is distinguished from Crohn's disease, another form of IBD, in that it is driven by a T helper type 2 (Th2) immune response. Oxazolone-induced colitis is a mouse model resembling UC presenting with inflammation limited to the distal colon and mixed neutrophil/lymphocyte infiltration in the superficial layer of the mucosa. The Th2 cytokines interleukin (IL)-4 and IL-13 are associated with the onset of oxazolone colitis and both signal through a common IL-4 receptor-alpha chain (IL-4R +-). Neutralizing these cytokines prevents or ameliorates disease significantly, while neutralizing IL-12 exacerbates disease symptoms. As many aspects of the mechanisms involving Th2 cytokines in colitis remain undefined, the aim of this study was to investigate the role of IL-4 and IL-13 and the receptors through which they signal in oxazolone-induced colitis. Previous studies have highlighted a role for IL-4 and IL-13 in mediating oxazolone colitis. We show that while IL-13-deficient BALB/c mice were protected from disease onset, IL-4R +- deficient BALB/c mice developed exacerbated disease symptoms

Targeting IL-13 as a Host-Directed Therapy Against Ulcerative Colitis

The role of interleukin-13 in mediating ulcerative colitis remains under scrutiny. Compelling evidence from both man and mouse suggests that IL-13 not only contributes to the pathology associated with disease but is also involved in mediating the inflammatory response. These studies have led to the approach of targeting IL-13 as a promising treatment strategy in alleviating ulcerative colitis disease. Despite this evidence, recent clinical trial data suggests that specifically blocking the receptor through which IL-13 signals, IL-4 receptor-alpha (IL-4Rα) in ulcerative colitis patients, is insufficient in protecting them from disease outcome. This challenges the importance of IL-13 as a therapeutic target. This review describes the role of IL-13 in ulcerative colitis and current treatment strategies that target IL-13. The potential role of IL-13 signaling independently of IL-4Rα in mediating ulcerative colitis is highlighted as an important consideration when targeting the signaling mechanisms of IL-13 for therapeutic approaches

Signalling C-Type lectin receptors, microbial recognition and immunity

This work was supported in part by the Wellcome Trust, Medical Research Council (UK) and the University of Cape Town. J.C. Hoving is a Carnegie Corporation postdoctoral researcher at the University of Cape Town. We apologize of all our colleagues whose important contributions we could not cite due to space constraints.Peer reviewedPublisher PD

The estimated burden of fungal disease in South Africa

Publication fees were paid via funding from a grant from Fonds.Peer reviewedPublisher PD

Correction: Delayed Goblet Cell Hyperplasia, Acetylcholine Receptor Expression, and Worm Expulsion in SMC-Specific IL-4Rα–Deficient Mice

Interleukin 4 receptor alpha (IL-4Ralpha) is essential for effective clearance of gastrointestinal nematode infections. Smooth muscle cells are considered to play a role in the type 2 immune response-driven expulsion of gastrointestinal nematodes. Previous studies have shown in vitro that signal transducer and activator of transcription 6 signaling in response to parasitic nematode infection significantly increases smooth muscle cell contractility. Inhibition of the IL-4Ralpha pathway inhibits this response. How this response manifests itself in vivo is unknown. In this study, smooth muscle cell IL-4Ralpha-deficient mice (SM-MHC(Cre)IL-4Ralpha(-/lox)) were generated and characterized to uncover any role for IL-4/IL-13 in this non-immune cell type in response to Nippostrongylus brasiliensis infection. IL-4Ralpha was absent from alpha-actin-positive smooth muscle cells, while other cell types showed normal IL-4Ralpha expression, thus demonstrating efficient cell-type-specific deletion of the IL-4Ralpha gene. N. brasiliensis-infected SM-MHC(Cre)IL-4Ralpha(-/lox) mice showed delayed ability to resolve infection with significantly prolonged fecal egg recovery and delayed worm expulsion. The delayed expulsion was related to a delayed intestinal goblet cell hyperplasia, reduced T helper 2 cytokine production in the mesenteric lymph node, and reduced M3 muscarinic receptor expression during infection. Together, these results demonstrate that in vivo IL-4Ralpha-responsive smooth muscle cells are beneficial for N. brasiliensis expulsion by coordinating T helper 2 cytokine responses, goblet hyperplasia, and acetylcholine responsiveness, which drive smooth muscle cell contractions

Deletion of IL-4Rα on CD4 T Cells Renders BALB/c Mice Resistant to Leishmania major Infection

Effector responses induced by polarized CD4(+) T helper 2 (Th2) cells drive nonhealing responses in BALB/c mice infected with Leishmania major. Th2 cytokines IL-4 and IL-13 are known susceptibility factors for L. major infection in BALB/c mice and induce their biological functions through a common receptor, the IL-4 receptor α chain (IL-4Rα). IL-4Rα–deficient BALB/c mice, however, remain susceptible to L. major infection, indicating that IL-4/IL-13 may induce protective responses. Therefore, the roles of polarized Th2 CD4(+) T cells and IL-4/IL-13 responsiveness of non-CD4(+) T cells in inducing nonhealer or healer responses have yet to be elucidated. CD4(+) T cell–specific IL-4Rα (Lck(cre)IL-4Rα(−/lox)) deficient BALB/c mice were generated and characterized to elucidate the importance of IL-4Rα signaling during cutaneous leishmaniasis in the absence of IL-4–responsive CD4(+) T cells. Efficient deletion was confirmed by loss of IL-4Rα expression on CD4(+) T cells and impaired IL-4–induced CD4(+) T cell proliferation and Th2 differentiation. CD8(+), γδ(+), and NK–T cells expressed residual IL-4Rα, and representative non–T cell populations maintained IL-4/IL-13 responsiveness. In contrast to IL-4Rα(−/lox) BALB/c mice, which developed ulcerating lesions following infection with L. major, Lck(cre)IL-4Rα(−/lox) mice were resistant and showed protection to rechallenge, similar to healer C57BL/6 mice. Resistance to L. major in Lck(cre)IL-4Rα(−/lox) mice correlated with reduced numbers of IL-10–secreting cells and early IL-12p35 mRNA induction, leading to increased delayed type hypersensitivity responses, interferon-γ production, and elevated ratios of inducible nitric oxide synthase mRNA/parasite, similar to C57BL/6 mice. These data demonstrate that abrogation of IL-4 signaling in CD4(+) T cells is required to transform nonhealer BALB/c mice to a healer phenotype. Furthermore, a beneficial role for IL-4Rα signaling in L. major infection is revealed in which IL-4/IL-13–responsive non-CD4(+) T cells induce protective responses

Emergomyces africanus in soil, South Africa

We detected Emergomyces africanus, a thermally dimorphic fungus that causes an HIV-associated systemic mycosis, by PCR in 18 (30%) of 60 soil samples from a wide range of habitats in South Africa. Direct and indirect culture techniques were unsuccessful. Experimental intraperitoneal inoculation of conidia induced murine disease

Delayed Goblet Cell Hyperplasia, Acetylcholine Receptor Expression, and Worm Expulsion in SMC-Specific IL-4Rα–Deficient Mice

Interleukin 4 receptor α (IL-4Rα) is essential for effective clearance of gastrointestinal nematode infections. Smooth muscle cells are considered to play a role in the type 2 immune response–driven expulsion of gastrointestinal nematodes. Previous studies have shown in vitro that signal transducer and activator of transcription 6 signaling in response to parasitic nematode infection significantly increases smooth muscle cell contractility. Inhibition of the IL-4Rα pathway inhibits this response. How this response manifests itself in vivo is unknown. In this study, smooth muscle cell IL-4Rα–deficient mice (SM-MHC(Cre)IL-4Rα(−/lox)) were generated and characterized to uncover any role for IL-4/IL-13 in this non–immune cell type in response to Nippostrongylus brasiliensis infection. IL-4Rα was absent from α-actin–positive smooth muscle cells, while other cell types showed normal IL-4Rα expression, thus demonstrating efficient cell-type–specific deletion of the IL-4Rα gene. N. brasiliensis–infected SM-MHC(Cre)IL-4Rα(−/lox) mice showed delayed ability to resolve infection with significantly prolonged fecal egg recovery and delayed worm expulsion. The delayed expulsion was related to a delayed intestinal goblet cell hyperplasia, reduced T helper 2 cytokine production in the mesenteric lymph node, and reduced M3 muscarinic receptor expression during infection. Together, these results demonstrate that in vivo IL-4Rα–responsive smooth muscle cells are beneficial for N. brasiliensis expulsion by coordinating T helper 2 cytokine responses, goblet hyperplasia, and acetylcholine responsiveness, which drive smooth muscle cell contractions

HpARI protein secreted by a helminth parasite suppresses interleukin-33

Infection by helminth parasites is associated with amelioration of allergic reactivity, but mechanistic insights into this association are lacking. Products secreted by the mouse parasite Heligmosomoides polygyrus suppress type 2 (allergic) immune responses through interference in the interleukin-33 (IL-33) pathway. Here, we identified H. polygyrus Alarmin Release Inhibitor (HpARI), an IL-33-suppressive 26-kDa protein, containing three predicted complement control protein (CCP) modules. In vivo, recombinant HpARI abrogated IL-33, group 2 innate lymphoid cell (ILC2) and eosinophilic responses to Alternaria allergen administration, and diminished eosinophilic responses to Nippostrongylus brasiliensis, increasing parasite burden. HpARI bound directly to both mouse and human IL-33 (in the cytokine's activated state) and also to nuclear DNA via its N-terminal CCP module pair (CCP1/2), tethering active IL-33 within necrotic cells, preventing its release, and forestalling initiation of type 2 allergic responses. Thus, HpARI employs a novel molecular strategy to suppress type 2 immunity in both infection and allergy. Osbourn et al identified HpARI, a protein secreted by a helminth parasite that is capable of suppressing allergic responses. HpARI binds to IL-33 (a critical inducer of allergy) and nuclear DNA, preventing the release of IL-33 from necrotic epithelial cells

Nippostrongylus-induced intestinal hypercontractility requires IL-4 receptor alpha-responsiveness by T cells in mice

Gut-dwelling helminthes induce potent IL-4 and IL-13 dominated type 2 T helper cell (T H 2) immune responses, with IL-13 production being essential for Nippostrongylus brasiliensis expulsion. This T H 2 response results in intestinal inflammation associated with local infiltration by T cells and macrophages. The resulting increased IL-4/IL-13 intestinal milieu drives goblet cell hyperplasia, alternative macrophage activation and smooth muscle cell hypercontraction. In this study we investigated how IL-4-promoted T cells contributed to the parasite induced effects in the intestine. This was achieved using pan T cell-specific IL-4 receptor alpha-deficient mice (iLck cre IL-4Rα −/lox ) and IL-4Rα-responsive control mice. Global IL-4Rα −/− mice showed, as expected, impaired type 2 immunity to N. brasiliensis . Infected T cell-specific IL-4Rα-deficient mice showed comparable worm expulsion, goblet cell hyperplasia and IgE responses to control mice. However, impaired IL-4-promoted T H 2 cells in T cell-specific IL-4Rα deficient mice led to strikingly reduced IL-4 production by mesenteric lymph node CD4 + T cells and reduced intestinal IL-4 and IL-13 levels, compared to control mice. This reduced IL-4/IL-13 response was associated with an impaired IL-4/IL-13-mediated smooth muscle cell hypercontractility, similar to that seen in global IL-4Rα −/− mice. These results demonstrate that IL-4-promoted T cell responses are not required for the resolution of a primary N. brasiliensis infection. However, they do contribute significantly to an important physiological manifestation of helminth infection; namely intestinal smooth muscle cell-driven hypercontractility