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

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

A global horizon scan of the future impacts of robotics and autonomous systems on urban ecosystems

Technology is transforming societies worldwide. A major innovation is the emergence of robotics and autonomous systems (RAS), which have the potential to revolutionize cities for both people and nature. Nonetheless, the opportunities and challenges associated with RAS for urban ecosystems have yet to be considered systematically. Here, we report the findings of an online horizon scan involving 170 expert participants from 35 countries. We conclude that RAS are likely to transform land use, transport systems and human–nature interactions. The prioritized opportunities were primarily centred on the deployment of RAS for the monitoring and management of biodiversity and ecosystems. Fewer challenges were prioritized. Those that were emphasized concerns surrounding waste from unrecovered RAS, and the quality and interpretation of RAS-collected data. Although the future impacts of RAS for urban ecosystems are difficult to predict, examining potentially important developments early is essential if we are to avoid detrimental consequences but fully realize the benefits

Delayed goblet cell hyperplasia, acetylcholine receptor expression, and worm expulsion in SMC-specific IL-4Ralpha-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

Antagonizing the alpha(4)beta(1) Integrin, but Not alpha(4)beta(7), Inhibits Leukocytic Infiltration of the Central Nervous System in Rhesus Monkey Experimental Autoimmune Encephalomyelitis

<p>The immune system is characterized by the preferential migration of lymphocytes through specific tissues (i.e., tissue tropism). Tissue tropism is mediated, in part, by the alpha(4) integrins expressed by T lymphocytes. The alpha(4)beta(1) integrin mediates migration of memory T lymphocytes into the CNS, whereas the alpha(4)beta(7) integrin mediates migration preferentially into gastrointestinal tissue. This paradigm was established primarily from investigations in rodents; thus, the objective of this investigation was to determine if blocking the alpha(4)beta(7) integrin exclusively would affect migration of T lymphocytes into the CNS of primates. The effects of the dual alpha(4)beta(1) and alpha(4)beta(7) antagonist natalizumab were compared with those of the alpha(4)beta(7) antagonist vedolizumab on experimental autoimmune encephalomyelitis in the rhesus monkey. Animals received an initial i.v. bolus of placebo, natalizumab (30 mg/kg), or vedolizumab (30 mg/kg) before intracutaneous immunization with recombinant human myelin oligodendrocyte glycoprotein and then Ab once weekly thereafter. Natalizumab prevented CNS inflammation and demyelination significantly (p <0.05), compared with time-matched placebo control animals, whereas vedolizumab did not inhibit these effects, despite saturating the alpha(4)beta(7) integrin in each animal for the duration of the investigation. These results demonstrate that blocking alpha(4)beta(7) exclusively does not inhibit immune surveillance of the CNS in primates. The Journal of Immunology, 2013, 190: 1961-1973.</p>

IL-4Rα Expression Is Impaired on Smooth Muscle Cells in SM-MHC^CreIL-4Rα^−/lox Mice

<div><p>(A) Genomic integrity of the SM-MHC^CreIL-4Rα^−/lox hemizygous mice was established by PCR.</p><p>(B) Smooth muscle cells were identified by intracellular α-actin (i) staining versus isotype control (ii). IL-4Rα surface expression was analyzed on gated α-actin–positive cells (iii).</p><p>(C) cDNA levels in trachea and small intestine of IL-4Rα^−/lox (black bars) and SM-MHC^CreIL-4Rα^−/lox (hatched bars). Data are derived from pooled tissue samples from three mice and are representative of two experiments.</p><p>(D) IL-4Rα expression on lymphocyte subpopulations of T cells and B cells is unaffected in SM-MHC^CreIL-4Rα^−/lox mice.</p></div

Intestinal Goblet Cell Hyperplasia Is Delayed in SM-MHC^CreIL-4Rα^−/lox Mice following Infection with N. brasiliensis

<p>Mucus-producing goblet cells were visualized using periodic−acid Schiff reagent staining at days 4, 7, and 10 PI. The number of hyperplasic goblet cells per five villi was calculated. Values indicate mean ± SD, with *, x, +, and ++ indicating significant differences between groups (<i>p</i> < 0.05). *Significant decrease in hyperplasic goblet cells in IL-4Rα^−/lox mice at day 10 PI compared to IL-4Rα^−/lox mice at day 7 PI. x, Significantly less hyperplasic goblet cells in IL-4Rα^−/− mice than in IL-4Rα^−/lox mice at day 7 PI. +, SM-MHC^CreIL-4Rα^−/lox mice had significantly more hyperplasic goblet cells at day 10 PI than did SM-MHC^CreIL-4Rα^−/lox mice at day 7 PI. ++, SM-MHC^CreIL-4Rα^−/lox mice had significantly more hyperplasic goblet cells than did IL-4Rα^−/lox mice at day 10 PI. Data are representative of four separate experiments.</p

Intestinal IL-13 Levels Are Disrupted in SM-MHC^CreIL-4Rα^−/lox Mice

<p>Intestinal supernatants were analyzed for IL-13 cytokine production by ELISA as described in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.0030001#s4" target="_blank">Materials and Methods</a>. *Significant difference (<i>p</i> < 0.05) from IL-4Rα^−/lox mice; +significant difference from day 10 PI IL-4Rα^−/− mice. Data are representative of three repeated experiments.</p

Role of Smooth Muscle IL-4Rα in N. brasiliensis Infection

<p>Solid arrows represent demonstrated effects of smooth muscle IL-4Rα on the host response to N. brasiliensis infection. Dotted arrows indicate other potential and/or likely interactions.</p

SM-MHC^CreIL-4Rα^−/lox Mice Have a Delayed Adult Worm Expulsion from the Intestine

<div><p>(A) N. brasiliensis egg production in infected mice was assessed daily from day 5 PI using the modified McMaster technique.</p><p>(B) Worm burden was established on days 4, 7, and 10 PIn by counting worms in intestines removed from infected mice.</p><p>(C) Serum IgE antibody responses in IL-4Rα^−/lox and SM-MHC^CreIL-4Rα^−/lox mice are equivalent. Serum from infected mice was taken on days 7 and 10 PI and analyzed for antibody production by ELISA as described in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.0030001#s4" target="_blank">Materials and Methods</a>. *Significant differences from IL-4Rα^−/lox mice (<i>p</i> < 0.05); data are representative of four separate experiments.</p></div