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Richard locksley

Christoph Schneider, Claire E O'Leary, Jakob von Moltke, Hong-Erh Liang, Qi Yan Ang, Peter J Turnbaugh, Sridhar Radhakrishnan, Michael Pellizzon, Averil Ma, Richard M Locksley
The small intestinal tuft cell-ILC2 circuit mediates epithelial responses to intestinal helminths and protists by tuft cell chemosensory-like sensing and IL-25-mediated activation of lamina propria ILC2s. Small intestine ILC2s constitutively express the IL-25 receptor, which is negatively regulated by A20 (Tnfaip3). A20 deficiency in ILC2s spontaneously triggers the circuit and, unexpectedly, promotes adaptive small-intestinal lengthening and remodeling. Circuit activation occurs upon weaning and is enabled by dietary polysaccharides that render mice permissive for Tritrichomonas colonization, resulting in luminal accumulation of acetate and succinate, metabolites of the protist hydrogenosome...
May 23, 2018: Cell
Pengfei Sui, Darin L Wiesner, Jinhao Xu, Yan Zhang, Jinwoo Lee, Steven Van Dyken, Amber Lashua, Chuyue Yu, Bruce S Klein, Richard M Locksley, Gail Deutsch, Xin Sun
Pulmonary neuroendocrine cells (PNECs) are rare airway epithelial cells whose function is poorly understood. Here we show that Ascl1 -mutant mice which have no PNECs exhibit severely blunted mucosal type 2 response in models of allergic asthma. PNECs reside in close proximity to group 2 innate lymphoid cells (ILC2s) near airway branch points. PNECs act through calcitonin gene-related peptide (CGRP) to stimulate ILC2s and elicit downstream immune responses. In addition, PNECs act through neurotransmitter gamma-aminobutyric acid (GABA) to induce goblet-cell hyperplasia...
March 29, 2018: Science
Justin I Odegaard, Min-Woo Lee, Yoshitaka Sogawa, Ambre M Bertholet, Richard M Locksley, David E Weinberg, Yuriy Kirichok, Rahul C Deo, Ajay Chawla
No abstract text is available yet for this article.
December 14, 2017: Cell
Priti B Singh, Heather H Pua, Hannah C Happ, Christoph Schneider, Jakob von Moltke, Richard M Locksley, Dirk Baumjohann, K Mark Ansel
MicroRNAs (miRNAs) exert powerful effects on immunity through coordinate regulation of multiple target genes in a wide variety of cells. Type 2 innate lymphoid cells (ILC2s) are tissue sentinel mediators of allergic inflammation. We established the physiological requirements for miRNAs in ILC2 homeostasis and immune function and compared the global miRNA repertoire of resting and activated ILC2s and T helper type 2 (TH 2) cells. After exposure to the natural allergen papain, mice selectively lacking the miR-17∼92 cluster in ILC2s displayed reduced lung inflammation...
December 4, 2017: Journal of Experimental Medicine
Richard Locksley
No abstract text is available yet for this article.
October 2017: Nature Reviews. Immunology
Adam K Savage, Hong-Erh Liang, Richard M Locksley
Group 3 innate lymphoid cells (ILC3s) are important for intestinal health, particularly in controlling inflammation in response to epithelial dysregulation, but their role during homeostasis remains less well understood. We generated IL-22 reporter mice to assess production of this key cytokine by ILC3s in the small intestine during development and under basal conditions. Although IL-22 is produced by a variety of lymphocyte populations, constitutively high IL-22 expression was limited to lymphoid-tissue inducer (LTi) cells residing in lymph node-like structures in the gut called solitary intestinal lymphoid tissues (SILT)...
September 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Andrew J Lechner, Ian H Driver, Jinwoo Lee, Carmen M Conroy, Abigail Nagle, Richard M Locksley, Jason R Rock
To investigate the role of immune cells in lung regeneration, we used a unilateral pneumonectomy model that promotes the formation of new alveoli in the remaining lobes. Immunofluorescence and single-cell RNA sequencing found CD115+ and CCR2+ monocytes and M2-like macrophages accumulating in the lung during the peak of type 2 alveolar epithelial stem cell (AEC2) proliferation. Genetic loss of function in mice and adoptive transfer studies revealed that bone marrow-derived macrophages (BMDMs) traffic to the lung through a CCL2-CCR2 chemokine axis and are required for optimal lung regeneration, along with Il4ra-expressing leukocytes...
July 6, 2017: Cell Stem Cell
Steven J Van Dyken, Hong-Erh Liang, Ram P Naikawadi, Prescott G Woodruff, Paul J Wolters, David J Erle, Richard M Locksley
The environmentally widespread polysaccharide chitin is degraded and recycled by ubiquitous bacterial and fungal chitinases. Although vertebrates express active chitinases from evolutionarily conserved loci, their role in mammalian physiology is unclear. We show that distinct lung epithelial cells secrete acidic mammalian chitinase (AMCase), which is required for airway chitinase activity. AMCase-deficient mice exhibit premature morbidity and mortality, concomitant with accumulation of environmentally derived chitin polymers in the airways and expression of pro-fibrotic cytokines...
April 20, 2017: Cell
Jakob von Moltke, Claire E O'Leary, Nora A Barrett, Yoshihide Kanaoka, K Frank Austen, Richard M Locksley
Group 2 innate lymphoid cells (ILC2s) and type 2 helper T cells (Th2 cells) are the primary source of interleukin 5 (IL-5) and IL-13 during type 2 (allergic) inflammation in the lung. In Th2 cells, T cell receptor (TCR) signaling activates the transcription factors nuclear factor of activated T cells (NFAT), nuclear factor κB (NF-κB), and activator protein 1 (AP-1) to induce type 2 cytokines. ILC2s lack a TCR and respond instead to locally produced cytokines such as IL-33. Although IL-33 induces AP-1 and NF-κB, NFAT signaling has not been described in ILC2s...
January 2017: Journal of Experimental Medicine
Steven J Van Dyken, Jesse C Nussbaum, Jinwoo Lee, Ari B Molofsky, Hong-Erh Liang, Joshua L Pollack, Rachel E Gate, Genevieve E Haliburton, Chun J Ye, Alexander Marson, David J Erle, Richard M Locksley
Group 2 innate lymphoid cells (ILC2s) and CD4+ type 2 helper T cells (TH 2 cells) are defined by their similar effector cytokines, which together mediate the features of allergic immunity. We found that tissue ILC2s and TH 2 cells differentiated independently but shared overlapping effector function programs that were mediated by exposure to the tissue-derived cytokines interleukin 25 (IL-25), IL-33 and thymic stromal lymphopoietin (TSLP). Loss of these three tissue signals did not affect lymph node priming, but abrogated the terminal differentiation of effector TH 2 cells and adaptive lung inflammation in a T cell-intrinsic manner...
December 2016: Nature Immunology
Haim Belinson, Adam K Savage, Douglas Fadrosh, Yien-Ming Kuo, Din Lin, Ricardo Valladares, Ysbrand Nusse, Anthony Wynshaw-Boris, Susan V Lynch, Richard M Locksley, Ophir D Klein
Homeostasis of the gastrointestinal (GI) tract is controlled by complex interactions between epithelial and immune cells and the resident microbiota. Here, we studied the role of Wnt signaling in GI homeostasis using Disheveled 1 knockout (Dvl1(-/-)) mice, which display an increase in whole gut transit time. This phenotype is associated with a reduction and mislocalization of Paneth cells and an increase in CD8(+) T cells in the lamina propria. Bone marrow chimera experiments demonstrated that GI dysfunction requires abnormalities in both epithelial and immune cells...
July 7, 2016: JCI Insight
Justin I Odegaard, Min-Woo Lee, Yoshitaka Sogawa, Ambre M Bertholet, Richard M Locksley, David E Weinberg, Yuriy Kirichok, Rahul C Deo, Ajay Chawla
For placental mammals, the transition from the in utero maternal environment to postnatal life requires the activation of thermogenesis to maintain their core temperature. This is primarily accomplished by induction of uncoupling protein 1 (UCP1) in brown and beige adipocytes, the principal sites for uncoupled respiration. Despite its importance, how placental mammals license their thermogenic adipocytes to participate in postnatal uncoupled respiration is not known. Here, we provide evidence that the "alarmin" IL-33, a nuclear cytokine that activates type 2 immune responses, licenses brown and beige adipocytes for uncoupled respiration...
August 11, 2016: Cell
Erin D Gordon, Richard M Locksley, John V Fahy
No abstract text is available yet for this article.
May 1, 2016: American Journal of Respiratory and Critical Care Medicine
Jakob von Moltke, Ming Ji, Hong-Erh Liang, Richard M Locksley
Parasitic helminths and allergens induce a type 2 immune response leading to profound changes in tissue physiology, including hyperplasia of mucus-secreting goblet cells and smooth muscle hypercontractility. This response, known as 'weep and sweep', requires interleukin (IL)-13 production by tissue-resident group 2 innate lymphoid cells (ILC2s) and recruited type 2 helper T cells (TH2 cells). Experiments in mice and humans have demonstrated requirements for the epithelial cytokines IL-33, thymic stromal lymphopoietin (TSLP) and IL-25 in the activation of ILC2s, but the sources and regulation of these signals remain poorly defined...
January 14, 2016: Nature
Ari B Molofsky, Frédéric Van Gool, Hong-Erh Liang, Steven J Van Dyken, Jesse C Nussbaum, Jinwoo Lee, Jeffrey A Bluestone, Richard M Locksley
Group 2 innate lymphoid cells (ILC2s) and regulatory T (Treg) cells are systemically induced by helminth infection but also sustain metabolic homeostasis in adipose tissue and contribute to tissue repair during injury. Here we show that interleukin-33 (IL-33) mediates activation of ILC2s and Treg cells in resting adipose tissue, but also after helminth infection or treatment with IL-2. Unexpectedly, ILC2-intrinsic IL-33 activation was required for Treg cell accumulation in vivo and was independent of ILC2 type 2 cytokines but partially dependent on direct co-stimulatory interactions via ICOSL-ICOS...
July 21, 2015: Immunity
Ari B Molofsky, Adam K Savage, Richard M Locksley
Interleukin-33 (IL-33) is a nuclear-associated cytokine of the IL-1 family originally described as a potent inducer of allergic type 2 immunity. IL-33 signals via the receptor ST2, which is highly expressed on group 2 innate lymphoid cells (ILC2s) and T helper 2 (Th2) cells, thus underpinning its association with helminth infection and allergic pathology. Recent studies have revealed ST2 expression on subsets of regulatory T cells, and for a role for IL-33 in tissue homeostasis and repair that suggests previously unrecognized interactions within these cellular networks...
June 16, 2015: Immunity
William E Seaman, Richard M Locksley, Michael J Welsh
No abstract text is available yet for this article.
May 20, 2015: Science Translational Medicine
Christian Schwartz, Ralf Willebrand, Silke Huber, Rudolf A Rupec, Davina Wu, Richard Locksley, David Voehringer
Eosinophils are associated with type 2 immune responses to allergens and helminths. They release various proinflammatory mediators and toxic proteins on activation and are therefore considered proinflammatory effector cells. Eosinophilia is promoted by the cytokines interleukin (IL)-3, IL-5, and granulocyte macrophage-colony-stimulating factor (GM-CSF) and can result from enhanced de novo production or reduced apoptosis. In this study, we show that only IL-5 induces differentiation of eosinophils from bone marrow precursors, whereas IL-5, GM-CSF, and to a lesser extent IL-3 promote survival of mature eosinophils...
June 18, 2015: Blood
Laurence E Cheng, Brandon M Sullivan, Lizett E Retana, Christopher D C Allen, Hong-Erh Liang, Richard M Locksley
Vertebrate immunity has evolved a modular architecture in response to perturbations. Allergic inflammation represents such a module, with signature features of antigen-specific IgE and tissue eosinophilia, although the cellular and molecular circuitry coupling these responses remains unclear. Here, we use genetic and imaging approaches in models of IgE-dependent eosinophilic dermatitis to demonstrate a requisite role for basophils. After antigenic inflammation, basophils initiate transmigration like other granulocytes but, upon activation via their high-affinity IgE receptor, alter their migratory kinetics to persist at the endothelium...
April 6, 2015: Journal of Experimental Medicine
Min-Woo Lee, Justin I Odegaard, Lata Mukundan, Yifu Qiu, Ari B Molofsky, Jesse C Nussbaum, Karen Yun, Richard M Locksley, Ajay Chawla
Type 2 innate lymphoid cells (ILC2s), an innate source of the type 2 cytokines interleukin (IL)-5 and -13, participate in the maintenance of tissue homeostasis. Although type 2 immunity is critically important for mediating metabolic adaptations to environmental cold, the functions of ILC2s in beige or brown fat development are poorly defined. We report here that activation of ILC2s by IL-33 is sufficient to promote the growth of functional beige fat in thermoneutral mice. Mechanistically, ILC2 activation results in the proliferation of bipotential adipocyte precursors (APs) and their subsequent commitment to the beige fat lineage...
January 15, 2015: Cell
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