Inflammation
Abstract
Psoriasis (PS) is a systemic, immune-mediated inflammatory disorder. However, the whole lymphocyte compartment and the potential pathologies of PS have not been fully characterized. In the present study, we examined whole lymphocyte subsets and signal transduction proteins using high-dimensional single-cell mass cytometry and a bioinformatics pipeline for an in-depth characterization of the immune cell subsets and protein profiles involved in pathways in the peripheral blood of patients with PS. We identified 15 major immune cell populations in T cell lineages, and characterized various CD3+CD4+T helper and CD3+CD8+T cytotoxic cell populations simultaneously across 24 leukocyte markers and 7 proteins related to the signal transduction pathways. High-dimensional analysis identified three new subsets that are abundant in PS peripheral blood, resembling CD3-CD4+ lymphoid tissue inducer cells, Tc17, and CD8+CXCR3+ Tregs. We confirmed the CD3-CD4+ cells, and their features and functions, in an independent PS cohort. The use of single-cell mass cytometry allows systemic-level characterization of lymphocyte subpopulations and dysregulated signaling pathways in the blood of patients with PS, identifying abnormalities of different immune cell subsets. We validated that the CD3-CD4+ cells had elevated OX40 and decreased FRA2 expression, which were positively associated with the psoriasis area and severity index.
Authors
Ruru Guo, Ting Zhang, Xinyu Meng, Zhen Lin, Jinran Lin, Yu Gong, Xuesong Liu, Yuetian Yu, Guilin Zhao, Xianting Ding, Xiaoxiang Chen, Liangjing Lu
Abstract
Although Type-2 (T2) induced epithelial dysfunction is likely to profoundly alter epithelial differentiation and repair in asthma, the mechanisms for these effects are poorly understood. A role for specific mucins, heavily N-glycosylated epithelial glycoproteins, in orchestrating epithelial cell fate in response to T2 stimuli has not previously been investigated. Levels of a sialylated MUC4β isoform were found to be increased in airway specimens from asthmatic patients, in association with T2 inflammation. We hypothesized that IL-13 would increase sialylation of MUC4β, thereby altering its function and that the β-galactoside α-2,6-sialyltranferase 1 (ST6GAL1) would regulate the sialylation. Using human biologic specimens and cultured primary human airway epithelial cells (HAECs), we demonstrated that IL-13 increased sialylation of MUC4β under control of ST6GAL1, and that both were increased in asthma, particularly in those with elevated T2 biomarkers. ST6GAL1 induced sialylation of MUC4β altered its lectin binding and secretion. Both ST6GAL1 and MUC4β inhibited epithelial cell proliferation while promoting goblet cell differentiation. These in vivo and in vitro data provide strong evidence for a critical role for ST6GAL1 induced sialylation of MUC4β in epithelial dysfunction associated with T2-High asthma, thereby identifying specific sialylation pathways as potential targets in asthma.
Authors
Xiuxia Zhou, Carol L. Kinlough, Rebecca P. Hughey, Mingzhu Jin, Hideki Inoue, Emily Etling, Brian D. Modena, Naftali Kaminski, Eugene R. Bleecker, Deborah A. Meyers, Nizar N. Jarjour, John B. Trudeau, Fernando Holguin, Anuradha Ray, Sally E. Wenzel
Abstract
Plexiform neurofibroma is a major contributor to morbidity in patients with neurofibromatosis type I (NF1). Macrophages and mast cells infiltrate neurofibroma, and data from mouse models implicate these leukocytes in neurofibroma development. Antiinflammatory therapy targeting these cell populations has been suggested as a means to prevent neurofibroma development. Here, we compare gene expression in Nf1-mutant nerves, which invariably form neurofibroma, and show disruption of neuron–glial cell interactions and immune cell infiltration to mouse models, which rarely progresses to neurofibroma with or without disruption of neuron–glial cell interactions. We find that the chemokine Cxcl10 is uniquely upregulated in NF1 mice that invariably develop neurofibroma. Global deletion of the CXCL10 receptor Cxcr3 prevented neurofibroma development in these neurofibroma-prone mice, and an anti–Cxcr3 antibody somewhat reduced tumor numbers. Cxcr3 expression localized to T cells and DCs in both inflamed nerves and neurofibromas, and Cxcr3 expression was necessary to sustain elevated macrophage numbers in Nf1-mutant nerves. To our knowledge, these data support a heretofore-unappreciated role for T cells and DCs in neurofibroma initiation.
Authors
Jonathan S. Fletcher, Jianqiang Wu, Walter J. Jessen, Jay Pundavela, Jacob A. Miller, Eva Dombi, Mi-Ok Kim, Tilat A. Rizvi, Kashish Chetal, Nathan Salomonis, Nancy Ratner
Abstract
Psoriasis is one of the most common skin inflammatory diseases worldwide. The vitamin D3 analog calcipotriol has been used alone or in combination with corticosteroids in treating plaque psoriasis, but how it suppresses psoriatic inflammation has not been fully understood. Using an experimental mouse psoriasis model, we show that topical calcipotriol inhibited the pivotal IL-23/IL-17 axis and neutrophil infiltration in psoriatic skin, and interestingly, such effects were mediated through the vitamin D receptor (VDR) in keratinocytes (KCs). We further reveal that IL-36α and IL-36γ, which have recently emerged as key players in psoriasis pathogenesis, were effectively repressed by calcipotriol via direct VDR signaling in mouse KCs. Accordingly, calcipotriol treatment suppressed IL-36α/γ expression in lesional skin from patients with plaque psoriasis, which was accompanied by a reduced IL-23/IL-17 expression. In contrast, dexamethasone indirectly reduced IL-36α/γ expression in mouse psoriatic skin through immune cells. Furthermore, we demonstrate that calcipotriol and dexamethasone, in combination, synergistically suppressed the expression of IL-36α/γ, IL-23, and IL-17 in the established mouse psoriasis. Our findings indicate that the combination of calcipotriol and corticosteroid efficiently disrupts the IL-36 and IL-23/IL-17 positive feedback loop, thus revealing a mechanism underlying the superior efficacy of calcipotriol and corticosteroid combination therapy for psoriasis.
Authors
Beatriz Germán, Ruicheng Wei, Pierre Hener, Christina Martins, Tao Ye, Cornelia Gottwick, Jianying Yang, Julien Seneschal, Katia Boniface, Mei Li
Abstract
Although the importance of the tumor immune environment for the modulation of tumorigenesis and tumor regression is becoming increasingly clear, most of the research related to tumor-immune therapies has focused on adaptive immune cells, while the role and regulation of innate leukocytes such as neutrophils remains controversial and less defined. Here we observed that the selective deletion of Tollip, a key innate immune-cell modulator, led to enhanced tumor immune surveillance in a chemically induced colorectal cancer model. Tollip-deficient neutrophils significantly elevated T cell activation through enhanced expression of the costimulatory molecule CD80, and reduced expression of the inhibitory molecule PD-L1. Mechanistically, Tollip deficiency increased STAT5 and reduced STAT1, the transcription factors responsible for the expression of CD80 and PD-L1, respectively. Through adoptive transfer, we demonstrate that Tollip-deficient neutrophils, but not Tollip-deficient monocytes, are sufficient to drive enhanced tumor immune surveillance and reduced colorectal cancer burden in vivo. Our data reveal a strategy for the reprogramming of neutrophil functions conducive for the enhancement of the antitumor immune environment.
Authors
Yao Zhang, Christina Lee, Shuo Geng, Liwu Li
Abstract
Acute kidney injury (AKI) is a common clinical condition of growing incidence. Patients who suffer severe AKI have a higher risk of developing interstitial fibrosis, chronic kidney disease, and end-stage renal disease later in life. Cellular senescence is a persistent cell cycle arrest and altered gene expression pattern evoked by multiple stressors. The number of senescent cells increases with age and even in small numbers these cells can induce chronic inflammation and fibrosis; indeed, in multiple organs including kidneys, the accumulation of such cells is a hallmark of aging. We hypothesized that cellular senescence might be induced in the kidney after injury and that this might contribute to progressive organ fibrosis. Testing this hypothesis, we found that tubular epithelial cells (TECs) in mice senesce within a few days of kidney injury and that this response is mediated by epithelial Toll-like and interleukin 1 receptors (TLR/IL-1R) of the innate immune system. Epithelial cell–specific inhibition of innate immune signaling in mice by knockout of myeloid differentiation 88 (Myd88) reduced fibrosis as well as damage to kidney tubules, and also prevented the accumulation of senescent TECs. Importantly, although inactivation of Myd88 after injury ameliorated fibrosis, it did not reduce damage to the tubules. Selectively induced apoptosis of senescent cells by two different approaches only partially reduced kidney fibrosis, without ameliorating damage to the tubules. Our data reveal a cell-autonomous role for epithelial innate immunity in controlling TEC senescence after kidney injury, and additionally suggest that early therapeutic intervention is required for effective reduction of long-term sequelae of AKI.
Authors
Heng Jin, Yan Zhang, Qiong Ding, Shan Shan Wang, Prerna Rastogi, Dao-Fu Dai, Dongmei Lu, Madison Purvis, Chao Cao, Angela Wang, Dingxiao Liu, Chongyu Ren, Sarah Elhadi, Ming-Chang Hu, Yanfen Chai, Diana Zepeda-Orozco, Judith Campisi, Massimo Attanasio
Abstract
Among other cells, macrophages regulate the inflammatory and reparative phases during wound healing but genetic determinants and detailed molecular pathways that modulate these processes are not fully elucidated. Here, we took advantage of normal variation in wound healing in 1,378 genetically outbred mice, and carried out macrophage RNA-sequencing profiling of mice with extreme wound healing phenotypes (i.e., slow and fast healers, n = 146 in total). The resulting macrophage coexpression networks were genetically mapped and led to the identification of a unique module under strong trans-acting genetic control by the Runx2 locus. This macrophage-mediated healing network was specifically enriched for cholesterol and fatty acid biosynthetic processes. Pharmacological blockage of fatty acid synthesis with cerulenin resulted in delayed wound healing in vivo, and increased macrophage infiltration in the wounded skin, suggesting the persistence of an unresolved inflammation. We show how naturally occurring sequence variation controls transcriptional networks in macrophages, which in turn regulate specific metabolic pathways that could be targeted in wound healing.
Authors
Marta Bagnati, Aida Moreno-Moral, Jeong-Hun Ko, Jérôme Nicod, Nathan Harmston, Martha Imprialou, Laurence Game, Jesus Gil, Enrico Petretto, Jacques Behmoaras
Polypropylene mesh implantation for hernia repair causes myeloid cell–driven persistent inflammation
Abstract
Polypropylene meshes that are commonly used for inguinal hernia repair may trigger granulomatous foreign body reactions. Here, we show that asymptomatic patients display mesh-associated inflammatory granulomas long after surgery, which are dominated by monocyte-derived macrophages expressing high levels of inflammatory activation markers. In mice, mesh implantation by the onlay technique induced rapid and strong myeloid cell accumulation, without substantial attenuation for up to 90 days. Myeloid cells segregated into distinct macrophage subsets with separate spatial distribution, activation profiles, and functional properties, showing a stable inflammatory phenotype in the tissue surrounding the biomaterial and a mixed, wound-healing phenotype in the surrounding stromal tissue. Protein mass spectrometry confirmed the inflammatory nature of the foreign body reaction, as characterized by cytokines, complement activation, and matrix-modulating factors. Moreover, immunoglobulin deposition increased over time around the implant, arguing for humoral immune responses in association with the cell-driven inflammation. Intravital multiphoton microscopy revealed a high motility and continuous recruitment of myeloid cells, which is partly dependent on the chemokine receptor CCR2. CCR2-dependent macrophages are particular drivers of fibroblast proliferation. Thus, our work functionally characterizes myeloid cell–dependent inflammation following mesh implantation, thereby providing insights into the dynamics and mechanisms of foreign body reactions to implanted biomaterials.
Authors
Felix Heymann, Klaus-Thilo von Trotha, Christian Preisinger, Petra Lynen-Jansen, Anjali A. Roeth, Melanie Geiger, Lukas Jonathan Geisler, Anna Katharina Frank, Joachim Conze, Tom Luedde, Christian Trautwein, Marcel Binnebösel, Ulf P. Neumann, Frank Tacke
Abstract
Osteoarthritis (OA) is a leading cause of disability, globally. Despite an emerging role for synovial inflammation in OA pathogenesis, attempts to target inflammation therapeutically have had limited success. A better understanding of the cellular and molecular processes occurring in the OA synovium is needed to develop novel therapeutics. We investigated macrophage phenotype and gene expression in synovial tissue of OA and inflammatory-arthritis (IA) patients. Compared with IA, OA synovial tissue contained higher but variable proportions of macrophages (P < 0.001). These macrophages exhibited an activated phenotype, expressing folate receptor-2 and CD86, and displayed high phagocytic capacity. RNA sequencing of synovial macrophages revealed 2 OA subgroups. Inflammatory-like OA (iOA) macrophages are closely aligned to IA macrophages and are characterized by a cell proliferation signature. In contrast, classical OA (cOA) macrophages display cartilage remodeling features. Supporting these findings, when compared with cOA, iOA synovial tissue contained higher proportions of macrophages (P < 0.01), expressing higher levels of the proliferation marker Ki67 (P < 0.01). These data provide new insight into the heterogeneity of OA synovial tissue and suggest distinct roles of macrophages in pathogenesis. Our findings could lead to the stratification of OA patients for suitable disease-modifying treatments and the identification of novel therapeutic targets.
Authors
Matthew J. Wood, Adam Leckenby, Gary Reynolds, Rachel Spiering, Arthur G. Pratt, Kenneth S. Rankin, John D. Isaacs, Muzlifah A. Haniffa, Simon Milling, Catharien M.U. Hilkens
Abstract
Host-commensal interactions are critical for the generation of robust inflammatory responses, yet the mechanisms leading to this effect remain poorly understood. Using a murine model of cytokine storm, we identified that host microbiota are required to sustain systemic TLR-driven immune responses. Mice treated with broad-spectrum antibiotics or raised in germ-free conditions responded normally to an initial TLR signal but failed to sustain production of proinflammatory cytokines following administration of repeated TLR signals in vivo. Mechanistically, host microbiota primed JAK signaling in myeloid progenitors to promote TLR-enhanced myelopoiesis, which is required for the accumulation of TLR-responsive monocytes. In the absence of TLR-enhanced monocytopoiesis, antibiotic-treated mice lost their ability to respond to repeated TLR stimuli and were protected from cytokine storm–induced immunopathology. These data reveal priming of TLR-enhanced myelopoiesis as a microbiota-dependent mechanism that regulates systemic inflammatory responses and highlight a role for host commensals in the pathogenesis of cytokine storm syndromes.
Authors
Lehn K. Weaver, Danielle Minichino, Chhanda Biswas, Niansheng Chu, Jung-Jin Lee, Kyle Bittinger, Sabrin Albeituni, Kim E. Nichols, Edward M. Behrens
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