Background: Hydroxymethyl-glutaryl-coenzyme A reductase inhibitors (‘statins’) are prescribed to millions of people. Statins are anti-inflammatory independent of their cholesterol-reducing effects. To date, most reports on the immune effects of statins have assayed a narrow array of variables and have focused on cell lines, rodent models, or patient cohorts. We sought to define the effect of rosuvastatin on the ‘immunome’ of healthy, normocholesterolemic subjects. Methods: Prospective study of rosuvastatin (20 mg/day x 28 days) in 18 statin-naïve adults with low density lipoprotein-cholesterol <130 mg/dL. A panel of >180 immune/biochemical/endocrinologic variables was measured at baseline, and days 14, 28, and 42 (14 days after drug withdrawal). Drug effect was evaluated using linear mixed effects models. Potential interactions between drug and baseline high-sensitivity C-reactive protein (hsCRP) were evaluated. Results: A wide array of immune measures changed (nominal p<0.05) during rosuvastatin treatment, although the changes were modest in magnitude and few met a false discovery rate of 0.05. Among changes noted were a concordant increase in pro-inflammatory cytokines (IFNγ, IL-1β, IL-5, IL-6, TNFα) and peripheral blood neutrophil frequency, and a decline in activated T regulatory cell frequency. Several drug effects were significantly modified by baseline hsCRP, and some did not resolve after drug withdrawal. Among other unexpected rosuvastatin effects were changes in erythrocyte indices, glucose-regulatory hormones, CD8+ T cells, and haptoglobin. Conclusion: Rosuvastatin induces modest changes in immunologic and metabolic measures in normocholesterolemic subjects, with several effects dependent upon baseline CRP. Future, larger studies are warranted to validate these changes and their physiological significance.
Peer W. F. Karmaus, Min Shi, Shira Perl, Angélique Biancotto, Julián Candia, Foo Cheung, Yuri Kotliarov, Neal Young, Michael B. Fessler
Severe asthma with fungal sensitization (SAFS) defines a subset of human asthmatics with allergy to one or more fungal species and difficult to control asthma. We have reported that human asthmatics sensitized to fungi have worse lung function and a higher degree of atopy, which was associated with higher IL-1RA levels in bronchoalveolar lavage fluid. IL-1RA further demonstrated a significant negative association with bronchial hyperresponsiveness to methacholine. Here, we show that IL-1α and IL-1β are elevated in both bronchoalveolar lavage fluid and sputum from human asthmatics sensitized to fungi, implicating an association with IL-1α, IL-1β or IL-1RA in fungal asthma severity. In an experimental model of fungal-associated allergic airway inflammation, we demonstrate that IL-1R1 signaling promotes type 1 (IFN-γ, CXCL9, CXCL10) and type 17 (IL-17A, IL-22) responses that were associated with neutrophilic inflammation and increased airway hyperreactivity. Each of these were exacerbated in the absence of IL-1RA. Administration of human recombinant IL-1RA (Kineret/Anakinra) during fungal-associated allergic airway inflammation improved airway hyperreactivity and lowered type 1 and type 17 responses. Taken together, these data suggest that IL-1 receptor signaling contributes to fungal asthma severity via immunopathogenic type 1 and type 17 responses and can be targeted for improving allergic asthma severity.
Matthew S. Godwin, Kristen M. Reeder, Jaleesa M. Garth, Jonathan P. Blackburn, MaryJane Jones, Zhihong Yu, Sadis Matalon, Annette T. Hastie, Deborah A. Meyers, Chad Steele
miR-511-3p, encoded by CD206/Mrc1, was demonstrated to reduce allergic inflammation and promote alternative (M2) macrophage polarization. Here, we sought to elucidate the fundamental mechanism by which miR-511-3p attenuates allergic inflammation and promotes macrophage polarization. Compared with wild-type mice, the allergen-challenged Mrc1-/- mice showed increased airway hyper-responsiveness (AHR) and inflammation. However, this increased AHR and inflammation were significantly attenuated when these mice were pre-transduced with adeno-associated virus (AAV)-miR-511-3p. Gene expression profiling of macrophages identified Ccl2 as one of the major genes that was highly expressed in M2 macrophages but antagonized by miR-511-3p. The interaction between miR-511-3p and Ccl2 was confirmed by in silico analysis and mRNA-miRNA pull-down assay. Further evidence for the inhibition of Ccl2 by miR-511-3p was given by reduced levels of Ccl2 in supernatants of miR-511-3p transduced macrophages and in bronchoalveolar lavage fluids of AAV-miR-511-3p-infected Mrc1-/- mice. Mechanistically, we demonstrated that Ccl2 promotes M1 macrophage polarization by activating RhoA signaling through Ccr2. The interaction between Ccr2 and RhoA was also supported by co-immunoprecipitation assay. Importantly, inhibition of RhoA signaling suppressed cockroach allergen-induced AHR and lung inflammation. These findings suggest a novel mechanism by which miR-511-3p regulates allergic inflammation and macrophage polarization by targeting Ccl2 and its downstream Ccr2/RhoA axis.
Danh C. Do, Jie Mu, Xia Ke, Karan Sachdeva, Zili Qin, Mei Wan, Faoud T. Ishmael, Peisong Gao
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathologic T cell-B cell interactions and autoantibody production. Defining the T cell populations that drive B cell responses in SLE may enable design of therapies that specifically target pathologic cell subsets. Here we evaluated the phenotypes of CD4+ T cells in the circulation of 52 SLE patients drawn from multiple cohorts and identified a highly expanded PD-1hi CXCR5- CD4+ T cell population. Cytometric, transcriptomic, and functional assays demonstrated that PD-1hi CXCR5- CD4+ T cells from SLE patients are T peripheral helper (Tph) cells, a CXCR5- T cell population that stimulates B cell responses via IL-21. The frequency of Tph cells, but not Tfh cells, correlated with both clinical disease activity and the frequency of CD11c+ B cells in SLE patients. PD-1hi CD4+ T cells were found within lupus nephritis kidneys and correlated with B cell numbers in kidney. Both IL-21 neutralization and CRISPR-mediated deletion of MAF abrogated the ability of Tph cells to induce memory B cell differentiation into plasmablasts in vitro. These findings identify Tph cells a highly expanded T cell population in SLE and suggest a key role for Tph cells in stimulating pathologic B cell responses.
Alexandra V. Bocharnikov, Joshua Keegan, Vanessa S. Wacleche, Ye Cao, Chamith Y. Fonseka, Guoxing Wang, Eric Muise, Kelvin X. Zhang, Arnon Arazi, Gregory Keras, Zhihan J. Li, Yujie Qu, Michael F. Gurish, Michelle Petri, Jill P. Buyon, Chaim Putterman, David Wofsy, Judith A. James, Joel M. Guthridge, Betty Diamond, Jennifer H. Anolik, Matthew F. Mackey, Stephen E. Alves, Peter A. Nigrovic, Karen H. Costenbader, Michael B. Brenner, James A. Lederer, Deepak A. Rao
Osteoarthritis (OA) is the leading cause of joint failure, yet the underlying mechanisms remain elusive, and no approved therapies that slow progression exist. Dysregulated integrin function was previously implicated in OA pathogenesis. However, the roles of integrin αVβ3 and the integrin-associated receptor CD47 in OA remain largely unknown. Here, transcriptomic and proteomic analyses of human and murine osteoarthritic tissues revealed dysregulated expression of αVβ3, CD47, and their ligands. Using genetically deficient mice and pharmacologic inhibitors, we showed that αVβ3, CD47, and the downstream signaling molecules Fyn and FAK are crucial to OA pathogenesis. MicroPET/CT imaging of a mouse model showed elevated ligand-binding capacities of integrin αVβ3 and CD47 in osteoarthritic joints. Further, our in vitro studies demonstrated that chondrocyte breakdown products, derived from articular cartilage of individuals with OA, induced αVβ3/CD47-dependent expression of inflammatory and degradative mediators, and revealed the downstream signaling network. Our findings identify a central role for dysregulated αVβ3 and CD47 signaling in OA pathogenesis and suggest that activation of αVβ3 and CD47 signaling in many articular cell types contributes to inflammation and joint destruction in OA. Thus, the data presented here provide a rationale for targeting αVβ3, CD47, and their signaling pathways as a disease-modifying therapy.
Qian Wang, Kazuhiro Onuma, Changhao Liu, Heidi Wong, Michelle S. Bloom, Eileen E. Elliott, Richard R.L. Cao, Nick Hu, Nithya Lingampalli, Orr Sharpe, Xiaoyan Zhao, Dong Hyun Sohn, Christin M. Lepus, Jeremy Sokolove, Rong Mao, Cecilia T. Cisar, Harini Raghu, Constance R. Chu, Nicholas J. Giori, Stephen B. Willingham, Susan S. Prohaska, Zhen Cheng, Irving L. Weissman, William H. Robinson
The roles of macrophages in orchestrating innate immunity through phagocytosis and T lymphocyte activation have been extensively investigated. Much less understood is the unexpected role of macrophages in direct tumor regression. Tumoricidal macrophages can indeed manifest cancer immunoediting activity in the absence of adaptive immunity. We investigated direct macrophage cytotoxicity in malignant pleural mesothelioma, a lethal cancer that develops from mesothelial cells of the pleural cavity after occupational asbestos exposure. In particular, we analyzed the cytotoxic activity of mouse RAW264.7 macrophages upon cell-cell contact with autologous AB1/AB12 mesothelioma cells. We show that macrophages killed mesothelioma cells by oxeiptosis via a mechanism involving enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27–specific (H3K27-specific) methyltransferase of the polycomb repressive complex 2 (PRC2). A selective inhibitor of EZH2 indeed impaired RAW264.7-directed cytotoxicity and concomitantly stimulated the PD-1 immune checkpoint. In the immunocompetent BALB/c model, RAW264.7 macrophages pretreated with the EZH2 inhibitor failed to control tumor growth of AB1 and AB12 mesothelioma cells. Blockade of PD-1 engagement restored macrophage-dependent antitumor activity. We conclude that macrophages can be directly cytotoxic for mesothelioma cells independent of phagocytosis. Inhibition of the PRC2 EZH2 methyltransferase reduces this activity because of PD-1 overexpression. Combination of PD-1 blockade and EZH2 inhibition restores macrophage cytotoxicity.
Malik Hamaidia, Hélène Gazon, Clotilde Hoyos, Gabriela Brunsting Hoffmann, Renaud Louis, Bernard Duysinx, Luc Willems
Tissue engineering is a promising approach to address organ shortages currently limiting clinical transplantation. “Off-the-shelf” engineered vascularized organs will likely use allogeneic endothelial cells (ECs) to construct microvessels required for graft perfusion. Vasculogenic ECs can be differentiated from committed progenitors (human endothelial colony forming cells or HECFCs) without risk of mutation or teratoma formation associated with reprogrammed stem cells. Like other ECs, these cells basally express both class I and class II major histocompatibility complex (MHC) molecules, bind donor-specific antibody (DSA), activate alloreactive T effector memory cells, and initiate rejection in the absence of donor leukocytes. We report here that CRISPR/Cas9-mediated dual ablation of β2-microglobulin and CIITA in HECFC-derived ECs eliminates both class I and II MHC expression while retaining EC functions and vasculogenic potential. Importantly, dually ablated ECs no longer bind human DSA or activate allogeneic CD4+ effector memory T cells and are resistant to killing by CD8+ alloreactive cytotoxic T lymphocytes in vitro and in vivo. Despite absent class I MHC molecules, these ECs do not activate or elicit cytotoxic activity from allogeneic natural killer cells. These data suggest that HECFC-derived ECs lacking MHC molecule expression can be utilized for engineering vascularized grafts that evade allorejection.
Jonathan Merola, Melanie Reschke, Richard W. Pierce, Lingfeng Qin, Susann Spindler, Tania Baltazar, Thomas D. Manes, Francesc Lopez-Giraldez, Guangxin Li, Laura G. Bracaglia, Catherine Xie, Nancy Kirkiles-Smith, W. Mark Saltzman, Gregory T. Tietjen, George Tellides, Jordan S. Pober
`NK cell–mediated regulation of antigen-specific T cells can contribute to and exacerbate chronic viral infection, but the protective mechanisms against NK cell–mediated attack on T cell immunity are poorly understood. Here, we show that progranulin (PGRN) can reduce NK cell cytotoxicity through reduction of NK cell expansion, granzyme B transcription, and NK cell–mediated lysis of target cells. Following infection with the lymphocytic choriomeningitis virus (LCMV), PGRN levels increased — a phenomenon dependent on the presence of macrophages and type I IFN signaling. Absence of PGRN in mice (Grn–/–) resulted in enhanced NK cell activity, increased NK cell–mediated killing of antiviral T cells, reduced antiviral T cell immunity, and increased viral burden, culminating in increased liver immunopathology. Depletion of NK cells restored antiviral immunity and alleviated pathology during infection in Grn–/– mice. In turn, PGRN treatment improved antiviral T cell immunity. Taken together, we identified PGRN as a critical factor capable of reducing NK cell–mediated attack of antiviral T cells.
Anfei Huang, Prashant V. Shinde, Jun Huang, Tina Senff, Haifeng C. Xu, Cassandra Margotta, Dieter Häussinger, Thomas E. Willnow, Jinping Zhang, Aleksandra A. Pandyra, Jörg Timm, Sascha Weggen, Karl S. Lang, Philipp A. Lang
Chagas disease is a life-long pathology resulting from Trypanosoma cruzi infection. It represents one of the most frequent causes of heart failure and sudden death in Latin America. Herein we provide evidence that aerobic glycolytic pathway activation in monocytes drives nitric oxide (NO) production, triggering tyrosine nitration (TN) on CD8 T cells and dysfunction in patients with chronic Chagas disease. Monocytes from patients exhibited higher frequency of hypoxia inducible factor (HIF)-1α and increased expression of its target genes/proteins. Non-classical monocytes are expanded in patients´ peripheral blood and represent an important source of NO. Monocytes entail CD8 T cell surface nitration since both the frequency of non-classical monocytes and that of NO-producing monocytes, positively correlated with the percentage of TN+ lymphocytes. Inhibition of glycolysis in (in vitro) infected peripheral blood mononuclear cells decreased the inflammatory properties of monocytes/macrophages diminishing the frequency of IL-1β- and NO-producing cells. In agreement, glycolysis inhibition reduced the percentage of TN+CD8 T cells improving their functionality. Altogether, these results clearly evidence that glycolysis governs oxidative stress on monocytes and modulates monocyte-T cell interplay in human chronic Chagas disease. Understanding the pathological immune mechanisms that sustains inflammatory environment in human pathology is key to design improved therapies.
Liliana María Sanmarco, Natalia Eberhardt, Gastón Bergero, Luz Piedad Quebrada Palacio, Pamela Martino Adami, Laura Marina Visconti, Ángel Ramón Minguez, Yolanda Hernández-Vasquez, Eugenio Antonio Carrera Silva, Laura Morelli, Miriam Postan, Maria Pilar Aoki
Long-term survivors post hematopoietic stem cell transplantation are at high risk of infection which accounts for one-third of all deaths. Little is known about the cause of inferior host defense after immune cell reconstitution. Here, we exploited a murine syngeneic bone marrow transplantation (BMT) model of late infection with gammaherpesvirus 68 (MHV-68) to determine the role of conventional dendritic cell (cDC) trafficking in adaptive immunity in BMT mice. Post infection, the expression of chemokine Ccl21 in the lung is reduced and the migration of cDCs into lung draining lymph nodes (dLNs) is impaired in BMT mice, limiting the opportunity for cDCs to prime Th cells in the dLNs. While cDC subsets are redundant in priming Th1 cells, Notch2 functions in cDC2s are required for priming increased Th17 responses in BMT mice and cDC1s can lessen this activity. Importantly, Th17 cells can be primed both in the lungs and dLNs, allowing for increased Th17 responses without optimum cDC trafficking in BMT mice. Taken together, impaired cDC trafficking in BMT mice reduces protective Th1 responses and allows increased pathogenic Th17 responses. Thus, we have revealed a previously unknown mechanism for BMT procedures to cause long-term inferior immune responses to herpes viral infection.
Carol A. Wilke, Matthew M. Chadwick, Paul R. Chan, Bethany B. Moore, Xiaofeng Zhou
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