IL-4/IL-13 independent goblet cell hyperplasia in experimental helminth infections

BACKGROUND: Intestinal mucus production by hyperplasic goblet cells is a striking pathological feature of many parasitic helminth infections and is related to intestinal protection and worm expulsion. Induction of goblet cell hyperplasia is associated with TH2 immune responses, which in helminth infections are controlled primarily by IL-13, and also IL-4. In the study presented here we examine the goblet cell hyperplasic response to three experimental parasitic helminth infections; namely Nippostrongylus brasiliensis, Syphacia obvelata and Schistosoma mansoni. RESULTS: As expected N. brasiliensis infection induced a strong goblet cell hyperplasia dependent on IL-4/IL-13/IL-4Ralpha expression. In contrast, and despite previously published transiently elevated IL-4/IL-13 levels, S. obvelata infections did not increase goblet cell hyperplasia in the colon. Furthermore, induction of goblet cell hyperplasia in response to S. mansoni eggs traversing the intestine was equivalent between BALB/c, IL-4/IL-13-/- and IL-4Ralpha-/- mice. CONCLUSION: Together these data demonstrate that intestinal goblet cell hyperplasia can be independent of TH2 immune responses associated with parasitic helminth infections

IL-4Rα-Independent Expression of Mannose Receptor and Ym1 by Macrophages Depends on their IL-10 Responsiveness

IL-4Rα-dependent responses are essential for granuloma formation and host survival during acute schistosomiasis. Previously, we demonstrated that mice deficient for macrophage-specific IL-4Rα (LysMcreIl4ra−/lox) developed increased hepatotoxicity and gut inflammation; whereas inflammation was restricted to the liver of mice lacking T cell-specific IL-4Rα expression (iLckcreIl4ra−/lox). In the study presented here we further investigated their role in liver granulomatous inflammation. Frequencies and numbers of macrophage, lymphocyte or granulocyte populations, as well as Th1/Th2 cytokine responses were similar in Schistosoma mansoni-infected LysMcreIl4ra−/lox liver granulomas, when compared to Il4ra−/lox control mice. In contrast, a shift to Th1 responses with high IFN-γ and low IL-4, IL-10 and IL-13 was observed in the severely disrupted granulomas of iLckcreIl4ra−/lox and Il4ra−/− mice. As expected, alternative macrophage activation was reduced in both LysMcreIl4ra−/lox and iLckcreIl4ra−/lox granulomas with low arginase 1 and heightened nitric oxide synthase RNA expression in granuloma macrophages of both mouse strains. Interestingly, a discrete subpopulation of SSChighCD11b+I-A/I-EhighCD204+ macrophages retained expression of mannose receptor (MMR) and Ym1 in LysMcreIl4ra−/lox but not in iLckcreIl4ra−/lox granulomas. While aaMφ were in close proximity to the parasite eggs in Il4ra−/lox control mice, MMR+Ym1+ macrophages in LysMcreIl4ra−/lox mice were restricted to the periphery of the granuloma, indicating that they might have different functions. In vivo IL-10 neutralisation resulted in the disappearance of MMR+Ym1+ macrophages in LysMcreIl4ra−/lox mice. Together, these results show that IL-4Rα-responsive T cells are essential to drive alternative macrophage activation and to control granulomatous inflammation in the liver. The data further suggest that in the absence of macrophage-specific IL-4Rα signalling, IL-10 is able to drive mannose receptor- and Ym1-positive macrophages, associated with control of hepatic granulomatous inflammation

Circulating Microbial Products and Acute Phase Proteins as Markers of Pathogenesis in Lymphatic Filarial Disease

Lymphatic filariasis can be associated with development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients. Dysregulated host inflammatory responses leading to systemic immune activation are thought to play a central role in filarial disease pathogenesis. We measured the plasma levels of microbial translocation markers, acute phase proteins, and inflammatory cytokines in individuals with chronic filarial pathology with (CP Ag+) or without (CP Ag−) active infection; with clinically asymptomatic infections (INF); and in those without infection (endemic normal [EN]). Comparisons between the two actively infected groups (CP Ag+ compared to INF) and those without active infection (CP Ag− compared to EN) were used preliminarily to identify markers of pathogenesis. Thereafter, we tested for group effects among all the four groups using linear models on the log transformed responses of the markers. Our data suggest that circulating levels of microbial translocation products (lipopolysaccharide and LPS-binding protein), acute phase proteins (haptoglobin and serum amyloid protein-A), and inflammatory cytokines (IL-1β, IL-12, and TNF-α) are associated with pathogenesis of disease in lymphatic filarial infection and implicate an important role for circulating microbial products and acute phase proteins

A Family of Helminth Molecules that Modulate Innate Cell Responses via Molecular Mimicry of Host Antimicrobial Peptides

Over the last decade a significant number of studies have highlighted the central role of host antimicrobial (or defence) peptides in modulating the response of innate immune cells to pathogen-associated ligands. In humans, the most widely studied antimicrobial peptide is LL-37, a 37-residue peptide containing an amphipathic helix that is released via proteolytic cleavage of the precursor protein CAP18. Owing to its ability to protect against lethal endotoxaemia and clinically-relevant bacterial infections, LL-37 and its derivatives are seen as attractive candidates for anti-sepsis therapies. We have identified a novel family of molecules secreted by parasitic helminths (helminth defence molecules; HDMs) that exhibit similar biochemical and functional characteristics to human defence peptides, particularly CAP18. The HDM secreted by Fasciola hepatica (FhHDM-1) adopts a predominantly α-helical structure in solution. Processing of FhHDM-1 by F. hepatica cathepsin L1 releases a 34-residue C-terminal fragment containing a conserved amphipathic helix. This is analogous to the proteolytic processing of CAP18 to release LL-37, which modulates innate cell activation by classical toll-like receptor (TLR) ligands such as lipopolysaccharide (LPS). We show that full-length recombinant FhHDM-1 and a peptide analogue of the amphipathic C-terminus bind directly to LPS in a concentration-dependent manner, reducing its interaction with both LPS-binding protein (LBP) and the surface of macrophages. Furthermore, FhHDM-1 and the amphipathic C-terminal peptide protect mice against LPS-induced inflammation by significantly reducing the release of inflammatory mediators from macrophages. We propose that HDMs, by mimicking the function of host defence peptides, represent a novel family of innate cell modulators with therapeutic potential in anti-sepsis treatments and prevention of inflammation

Interleukin 13-mediated colitis in the absence of IL-4Rα signalling.

Sufficient evidence points to interleukin 13 (IL-13) as an important pathological factor in UC and raises hopes to a promising new treatment strategy.1–3 However, the outcomes of two recent clinical trials, both published in Gut 2015, suggest otherwise.4 ,5 A commentary published in the same issue described these results as crushing the enthusiasm for anti-IL-13 treatment in UC.6 In this letter, we show evidence that the disease outcome is determined by the type of signalling pathway used by IL-13 in mice. Therefore, we suggest that directly blocking IL-13 remains a potential treatment strategy for a subset of patients with UC that have elevated tissue IL-13 production

IL-4R{alpha}-responsive smooth muscle cells increase intestinal hypercontractility and contribute to resistance during acute Schistosomiasis.

Interleukin-(IL)-4 and IL-13 signal through heterodimeric receptors containing a common IL-4 receptor-alpha (IL-4Ralpha) subunit, which is important for protection against helminth infections, including schistosomiasis. Previous studies demonstrated important roles for IL-4Ralpha-responsive hematopoietic cells, including T cells and macrophages in schistosomiasis. In this study, we examined the role of IL-4Ralpha responsiveness by nonhematopoietic smooth muscle cells during experimental acute murine schistosomiasis. Comparative Schistosoma mansoni infection studies with smooth muscle cell-specific IL-4Ralpha-deficient (SM-MHC(cre)IL-4Ralpha(-/flox)) mice, heterozygous control (IL-4Ralpha(-/flox)) mice, and global IL-4Ralpha-deficient (IL-4Ralpha(-/-)) mice were conducted. S. mansoni-infected SM-MHC(cre)IL-4Ralpha(-/flox) mice showed increased weight loss and earlier mortalities compared with IL-4Ralpha(-/flox) mice, despite comparable T(H)2/type 2 immune responses. In contrast to highly susceptible IL-4Ralpha-deficient mice, increased susceptibility in SM-MHC(cre)IL-4Ralpha(-/flox) mice was not accompanied by intestinal tissue damage and subsequent sepsis. However, both susceptible mutant mouse strains failed to efficiently expel eggs, demonstrated by egg reduction in the feces compared with control mice. Reduced egg expulsion was accompanied by impaired IL-4/IL-13-mediated hypercontractile intestinal responses, which was present in the more resistant control mice. Together, we conclude that IL-4Ralpha responsiveness by smooth muscle cells and subsequent IL-4- and IL-13-mediated hypercontractility are required for host protection during acute schistosomiasis to efficiently expel S. mansoni eggs and to prevent premature mortality

IL-4/IL-13 independent goblet cell hyperplasia in experimental helminth infections-0

Open bar) and IL-4/IL-13(gray bar) mice 7 days and 10 days PI in small intestine sections. B) Intestinal adult worm burden 7 and 10 days post infection. Data representative of two experiments are shown. Data are means of four mice per group ± SEM. * < 0.05; *** < 0.001 (significantly different from naïve mice).<p><b>Copyright information:</b></p><p>Taken from "IL-4/IL-13 independent goblet cell hyperplasia in experimental helminth infections"</p><p>http://www.biomedcentral.com/1471-2172/9/11</p><p>BMC Immunology 2008;9():11-11.</p><p>Published online 28 Mar 2008</p><p>PMCID:PMC2329604.</p><p></p

IL-4/IL-13 independent goblet cell hyperplasia in experimental helminth infections-4

Open bar) and IL-4/IL-13(gray bar) mice 7 days and 10 days PI in small intestine sections. B) Intestinal adult worm burden 7 and 10 days post infection. Data representative of two experiments are shown. Data are means of four mice per group ± SEM. * < 0.05; *** < 0.001 (significantly different from naïve mice).<p><b>Copyright information:</b></p><p>Taken from "IL-4/IL-13 independent goblet cell hyperplasia in experimental helminth infections"</p><p>http://www.biomedcentral.com/1471-2172/9/11</p><p>BMC Immunology 2008;9():11-11.</p><p>Published online 28 Mar 2008</p><p>PMCID:PMC2329604.</p><p></p

IL-4/IL-13 independent goblet cell hyperplasia in experimental helminth infections-3

Bar) and IL-4/IL-13(gray bar) mice at 8 weeks PI. Data are pooled from 2 to 4 individual experiments. Data are means of these experiments ± SEM. (B) Quantification of goblet cell number per villus in colon of naïve mice and 8 weeks PI from BALB/c (solid bar), IL-4Rα(open bar) and IL-4/IL-13(gray bar) mice. Data representative of three experiments are shown. * < 0.05 (significantly different from naïve mice). (C) Photomicrograph of colon from BALB/c, IL-4Rαand IL-4/IL-13. Representative pictures of colon sections are shown from both naïve (i) and infected mice at 8 weeks PI (ii). Sections were stained with PAS to identify goblet cells. 100× magnification<p><b>Copyright information:</b></p><p>Taken from "IL-4/IL-13 independent goblet cell hyperplasia in experimental helminth infections"</p><p>http://www.biomedcentral.com/1471-2172/9/11</p><p>BMC Immunology 2008;9():11-11.</p><p>Published online 28 Mar 2008</p><p>PMCID:PMC2329604.</p><p></p

IL-4/IL-13 independent goblet cell hyperplasia in experimental helminth infections-1

Of colon sections are shown from both naïve (i) and pinworm infected mice at 7 (ii) and 14 days PI (iii). Sections were stained with PAS to identify goblet cells. 100× magnification. (B) Quantification of goblet cells per crypt in colon 7 and 14 days PI in BALB/c (solid bar), IL-4Rα(open bar) and IL-4/IL-13(gray bar). Data representative of two experiments are shown. Data are means of four mice per group ± SEM. (C) dependent IL-4 secretion from anti-CD3 restimulated splenocytes. BALB/c (solid bar), IL-4Rα(open bar). **, P < 0.01 (significantly different from naive mice). Data representative of two experiments showing means for four mice/group ± SD.<p><b>Copyright information:</b></p><p>Taken from "IL-4/IL-13 independent goblet cell hyperplasia in experimental helminth infections"</p><p>http://www.biomedcentral.com/1471-2172/9/11</p><p>BMC Immunology 2008;9():11-11.</p><p>Published online 28 Mar 2008</p><p>PMCID:PMC2329604.</p><p></p