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Richard locksley

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 (TH2 cells) are defined by their similar effector cytokines, which together mediate the features of allergic immunity. We found that tissue ILC2s and TH2 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 TH2 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
Jennifer K Bando, Hong-Erh Liang, Richard M Locksley
Fetal lymphoid tissue inducer (LTi) cells are required for lymph node and Peyer's patch (PP) organogenesis, but where these specialized group 3 innate lymphoid cells (ILC3s) develop remains unclear. Here, we identify extrahepatic arginase-1(+) Id2(+) fetal ILC precursors that express a transitional developmental phenotype (ftILCPs) and differentiate into ILC1s, ILC2s and ILC3s in vitro. These cells populate the intestine by embryonic day (E) 13.5 and, before PP organogenesis (E14.5-15), are broadly dispersed in the proximal gut, correlating with regions where PPs first develop...
February 2015: Nature Immunology
Jakob von Moltke, Richard M Locksley
Innate type 2 immune cells are activated in response to helminths, allergens, and certain types of proteases and particulates. Recently, innate type 2 immune pathways have also been implicated in protective host responses to homeostatic perturbations, such as metabolic dysfunction, atherosclerosis, and tissue injury. In this context, innate type 2 cytokines stimulate local tissues, recruit eosinophils, and alternatively activate macrophages to restore homeostasis. As the major source of innate interleukin (IL)-5 and IL-13, group 2 innate lymphoid cells are positioned to initiate and maintain homeostatic type 2 responses...
December 2014: Current Opinion in Immunology
Laurence E Cheng, Richard M Locksley
Allergic inflammation is associated closely with parasite infection but also asthma and other common allergic diseases. Despite the engagement of similar immunologic pathways, parasitized individuals often show no outward manifestations of allergic disease. In this perspective, we present the thesis that allergic inflammatory responses play a primary role in regulating circadian and environmental inputs involved with tissue homeostasis and metabolic needs. Parasites feed into these pathways and thus engage allergic inflammation to sustain aspects of the parasitic life cycle...
November 20, 2014: Cold Spring Harbor Perspectives in Biology
Frédéric Van Gool, Ari B Molofsky, Malika M Morar, Michelle Rosenzwajg, Hong-Erh Liang, David Klatzmann, Richard M Locksley, Jeffrey A Bluestone
Interleukin (IL)-2 promotes regulatory T-cell development and function, and treatment with IL-2 is being tested as therapy for some autoimmune diseases. However, patients receiving IL-2 treatment also experience eosinophilia due to an unknown mechanism. Here, we show that patients receiving low-dose IL-2 have elevated levels of serum IL-5, and this correlates with their degree of eosinophilia. In mice, low-dose IL-2-anti-IL-2 antibody complexes drove group 2 innate lymphoid cells (ILC2) to produce IL-5 and proliferate...
December 4, 2014: Blood
Yifu Qiu, Khoa D Nguyen, Justin I Odegaard, Xiaojin Cui, Xiaoyu Tian, Richard M Locksley, Richard D Palmiter, Ajay Chawla
Beige fat, which expresses the thermogenic protein UCP1, provides a defense against cold and obesity. Although a cold environment is the physiologic stimulus for inducing beige fat in mice and humans, the events that lead from the sensing of cold to the development of beige fat remain poorly understood. Here, we identify the efferent beige fat thermogenic circuit, consisting of eosinophils, type 2 cytokines interleukin (IL)-4/13, and alternatively activated macrophages. Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced biogenesis of beige fat...
June 5, 2014: Cell
Michael L Patnode, Jennifer K Bando, Matthew F Krummel, Richard M Locksley, Steven D Rosen
Eosinophil accumulation is a defining feature of the immune response to parasitic worm infection. Tissue-resident cells, such as epithelial cells, are thought to initiate eosinophil recruitment. However, direct recognition of worms by eosinophils has not been explored as a mechanism for amplifying eosinophil accumulation. Here, we report that eosinophils rapidly migrate toward diverse nematode species in three-dimensional culture. These include the mammalian parasite Nippostrongylus brasiliensis and the free-living nematode Caenorhabditis elegans...
June 30, 2014: Journal of Experimental Medicine
Evan M O'Dea, Nansalmaa Amarsaikhan, Hongtao Li, Joshua Downey, Emery Steele, Steven J Van Dyken, Richard M Locksley, Steven P Templeton
In patients infected with the fungus Aspergillus fumigatus, Th1 responses are considered protective, while Th2 responses are associated with increased morbidity and mortality. How host-pathogen interactions influence the development of these protective or detrimental immune responses is not clear. We compared lung immune responses to conidia from two fungal isolates that expressed different levels of the fungal cell wall component chitin. We observed that repeated aspirations of the high-chitin-expressing isolate Af5517 induced increased airway eosinophilia in the lungs of recipient mice compared to the level of eosinophilia induced by isolate Af293...
August 2014: Infection and Immunity
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