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Kornfield JM, Bright H, Drake MG. Touching a Nerve: Neuroimmune Interactions in Asthma. Immunol Rev 2025; 331:e70025. [PMID: 40186378 DOI: 10.1111/imr.70025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 03/04/2025] [Accepted: 03/21/2025] [Indexed: 04/07/2025]
Abstract
Asthma is an inflammatory airway disease characterized by excessive bronchoconstriction and airway hyperresponsiveness. Airway nerves play a crucial role in regulating these processes. In asthma, interactions between inflammatory cells and nerves result in nerve dysfunction, which worsens airway function. This review discusses new insights regarding the role of airway nerves in healthy lungs and examines how communication between nerves and leukocytes, including eosinophils, mast cells, dendritic cells, and innate lymphoid cells, contributes to nerve dysfunction and the worsening of airway disease. Clinical implications and therapeutic opportunities presented by neuroimmune interactions are also addressed.
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Affiliation(s)
- James M Kornfield
- Division of Pulmonary, Allergy, and Critical Care, Oregon Health and Science University, Portland, Oregon, USA
| | - Hoyt Bright
- Division of Pulmonary, Allergy, and Critical Care, Oregon Health and Science University, Portland, Oregon, USA
| | - Matthew G Drake
- Division of Pulmonary, Allergy, and Critical Care, Oregon Health and Science University, Portland, Oregon, USA
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Al Mamun A, Shao C, Geng P, Wang S, Xiao J. Recent advances in the role of neuroregulation in skin wound healing. BURNS & TRAUMA 2025; 13:tkae072. [PMID: 39872039 PMCID: PMC11770601 DOI: 10.1093/burnst/tkae072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 10/24/2024] [Accepted: 11/01/2024] [Indexed: 01/29/2025]
Abstract
Neuroregulation during skin wound healing involves complex interactions between the nervous system and intricate tissue repair processes. The skin, the largest organ, depends on a complex system of nerves to manage responses to injury. Recent research has emphasized the crucial role of neuroregulation in maximizing wound healing outcomes. Recently, researchers have also explained the interactive contact between the peripheral nervous system and skin cells during the different phases of wound healing. Neurotransmitters and neuropeptides, once observed as simple signalling molecules, have since been recognized as effective regulators of inflammation, angiogenesis, and cell proliferation. The significance of skin innervation and neuromodulators is underscored by the delayed wound healing observed in patients with diabetes and the regenerative capabilities of foetal skin. Foetal skin regeneration is influenced by the neuroregulatory environment, immature immune system, abundant growth factors, and increased pluripotency of cells. Foetal skin cells exhibit greater flexibility and specialized cell types, and the extracellular matrix composition promotes regeneration. The extracellular matrix composition of foetal skin promotes regeneration, making it more capable than adult skin because neuroregulatory signals affect skin regeneration. The understanding of these systems can facilitate the development of therapeutic strategies to alter the nerve supply to the skin to enhance the process of wound healing. Neuroregulation is being explored as a potential therapeutic strategy for enhancing skin wound repair. Bioelectronic strategies and neuromodulation techniques can manipulate neural signalling, optimize the neuroimmune axis, and modulate inflammation. This review describes the function of skin innervation in wound healing, emphasizing the importance of neuropeptides released by sensory and autonomic nerve fibres. This article discusses significant discoveries related to neuroregulation and its impact on skin wound healing.
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Affiliation(s)
- Abdullah Al Mamun
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Chuxiao Shao
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
| | - Peiwu Geng
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
| | - Shuanghu Wang
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
| | - Jian Xiao
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- Department of Wound Healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
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Chen X, Jin Z, Zhou P, Xie T, Jiang F, Tang Q. Changes of CD8 +CD28 - Tregs and Gamma-Delta-T-cells in a Neonate with Intrauterine Cytomegalovirus Infection: A Case Report. BMC Pediatr 2024; 24:587. [PMID: 39285316 PMCID: PMC11403953 DOI: 10.1186/s12887-024-05051-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 09/03/2024] [Indexed: 09/22/2024] Open
Abstract
BACKGROUND Congenital cytomegalovirus (cCMV) infection can lead to a range of adverse outcomes. The majority of cCMV neonates with clinical symptoms are infected postnatally; however, established cases of intrauterine infection are uncommon, resulting in a paucity of reports on clinical findings and lymphocytes expression in CMV-infected neonates. CASE PRESENTATION We followed a neonate with cCMV infection from the onset of hospitalization to several months of follow-up. This infant was intrauterine CMV-positive in the amniotic fluid of the mother at 21 weeks' gestation and received intravenous ganciclovir infusion and sequential oral valganciclovir after birth. The typical clinical signs manifested in the nervous system, liver, and peripheral blood and were documented during the hospitalizaion period and up to the follow-up visit. Flow cytometry was employed to examine the expression of T cells, their subsets, and the associated cytokines in peripheral blood samples at various time points. The flow data for the cCMV neonate were compared with those of the controls at each time point. Following treatment, clinical symptoms improved and the infant became CMV negative. However, developmental delays occurred later in life. The proportion of CD8+CD28- Tregs in the peripheral blood of the neonate with congenital CMV infection was higher than that in the controls at the three time points. The expression levels of perforin and granzyme B secreted by γδ T cells (Vδ1 and Vδ2 T cells), increased during the course of hospitalization until follow-up and were higher than those in the controls at the three time points. CONCLUSIONS Despite the alleviation of clinical symptoms, developmental delay in later life remains inevitable in this intrauterine cCMV neonate. CD8+CD28- Tregs and Vδ1 and Vδ2 T cells secreting perforin and granzyme B may be involved in congenital CMV infection, although this hypothesis requires validation in a larger study. This report may contribute to our understanding of the effect of current treatment and the immune status of intrauterine cCMV-infected neonates.
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Affiliation(s)
- Xian Chen
- Department of Laboratory Medicine, Shenzhen Baoan Women's and Children's Hospital, Shenzhen, China
| | - Zhenchao Jin
- Department of Neonatology, Shenzhen Baoan Women's and Children's Hospital, Shenzhen, China
| | - Ping Zhou
- Department of Neonatology, Shenzhen Baoan Women's and Children's Hospital, Shenzhen, China
| | - Tingyan Xie
- Research Laboratory, Shenzhen Baoan Women's and Children's Hospital, Shenzhen, China
| | - Fan Jiang
- Department of Laboratory Medicine, Shenzhen Baoan Women's and Children's Hospital, Shenzhen, China
| | - Quan Tang
- Research Laboratory, Shenzhen Baoan Women's and Children's Hospital, Shenzhen, China.
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Rao IH, Waller EK, Dhamsania RK, Chandrasekaran S. Gene Expression Analysis Links Autocrine Vasoactive Intestinal Peptide and ZEB1 in Gastrointestinal Cancers. Cancers (Basel) 2023; 15:3284. [PMID: 37444395 DOI: 10.3390/cancers15133284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/12/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
VIP (vasoactive intestinal peptide) is a 28-amino acid peptide hormone expressed by cancer and the healthy nervous system, digestive tract, cardiovascular, and immune cell tissues. Many cancers express VIP and its surface receptors VPAC1 and VPAC2, but the role of autocrine VIP signaling in cancer as a targetable prognostic and predictive biomarker remains poorly understood. Therefore, we conducted an in silico gene expression analysis to study the mechanisms of autocrine VIP signaling in cancer. VIP expression from TCGA PANCAN tissue samples was analyzed against the expression levels of 760 cancer-associated genes. Of the 760 genes, 10 (MAPK3, ZEB1, TEK, NOS2, PTCH1 EIF4G1, GMPS, CDK2, RUVBL1, and TIMELESS) showed statistically meaningful associations with the VIP (Pearson's R-coefficient > |0.3|; p < 0.05) across all cancer histologies. The strongest association with the VIP was for the epithelial-mesenchymal transition regulator ZEB1 in gastrointestinal malignancies. Similar positive correlations between the VIP and ZEB1 expression were also observed in healthy gastrointestinal tissues. Gene set analysis indicates the VIP is involved in the EMT and cell cycle pathways, and a high VIP and ZEB1 expression is associated with higher median estimate and stromal scores These findings uncover novel mechanisms for VIP- signaling in cancer and specifically suggest a role for VIP as a biomarker of ZEB1-mediated EMT. Further studies are warranted to characterize the specific mechanism of this interaction.
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Affiliation(s)
- Ishani H Rao
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Edmund K Waller
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Rohan K Dhamsania
- Philadelphia College of Osteopathic Medicine (PCOM)-Georgia Campus, Suwanee, GA 30024, USA
| | - Sanjay Chandrasekaran
- Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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Moon S, Hong J, Go S, Kim BS. Immunomodulation for Tissue Repair and Regeneration. Tissue Eng Regen Med 2023; 20:389-409. [PMID: 36920675 PMCID: PMC10219918 DOI: 10.1007/s13770-023-00525-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 01/11/2023] [Accepted: 01/26/2023] [Indexed: 03/16/2023] Open
Abstract
Various immune cells participate in repair and regeneration following tissue injury or damage, orchestrating tissue inflammation and regeneration processes. A deeper understanding of the immune system's involvement in tissue repair and regeneration is critical for the development of successful reparatory and regenerative strategies. Here we review recent technologies that facilitate cell-based and biomaterial-based modulation of the immune systems for tissue repair and regeneration. First, we summarize the roles of various types of immune cells in tissue repair. Second, we review the principle, examples, and limitations of regulatory T (Treg) cell-based therapy, a representative cell-based immunotherapy. Finally, we discuss biomaterial-based immunotherapy strategies that aim to modulate immune cells using various biomaterials for tissue repair and regeneration.
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Affiliation(s)
- Sangjun Moon
- School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Jihye Hong
- Interdisciplinary Program for Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Seokhyeong Go
- Interdisciplinary Program for Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Byung-Soo Kim
- School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea.
- Interdisciplinary Program for Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea.
- Institute of Chemical Processes, Institute of Engineering Research, BioMAX, Seoul National University, Seoul, 08826, Republic of Korea.
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Sympathetic System in Wound Healing: Multistage Control in Normal and Diabetic Skin. Int J Mol Sci 2023; 24:ijms24032045. [PMID: 36768369 PMCID: PMC9916402 DOI: 10.3390/ijms24032045] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/14/2023] [Accepted: 01/18/2023] [Indexed: 01/22/2023] Open
Abstract
In this review, we discuss sympathetic regulation in normal and diabetic wound healing. Experimental denervation studies have confirmed that sympathetic nerve endings in skin have an important and complex role in wound healing. Vasoconstrictor neurons secrete norepinephrine (NE) and neuropeptide Y (NPY). Both mediators decrease blood flow and interact with inflammatory cells and keratinocytes. NE acts in an ambiguous way depending on receptor type. Beta2-adrenoceptors could be activated near sympathetic endings; they suppress inflammation and re-epithelialization. Alpha1- and alpha2-adrenoceptors induce inflammation and activate keratinocytes. Sudomotor neurons secrete acetylcholine (ACh) and vasoactive intestinal peptide (VIP). Both induce vasodilatation, angiogenesis, inflammation, keratinocytes proliferation and migration. In healthy skin, all effects are important for successful healing. In treatment of diabetic ulcers, mediator balance could be shifted in different ways. Beta2-adrenoceptors blockade and nicotinic ACh receptors activation are the most promising directions in treatment of diabetic ulcers with neuropathy, but they require further research.
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Filardy AA, Ferreira JRM, Rezende RM, Kelsall BL, Oliveira RP. The intestinal microenvironment shapes macrophage and dendritic cell identity and function. Immunol Lett 2023; 253:41-53. [PMID: 36623708 PMCID: PMC9907447 DOI: 10.1016/j.imlet.2023.01.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 12/12/2022] [Accepted: 01/04/2023] [Indexed: 01/09/2023]
Abstract
The gut comprises the largest body interface with the environment and is continuously exposed to nutrients, food antigens, and commensal microbes, as well as to harmful pathogens. Subsets of both macrophages and dendritic cells (DCs) are present throughout the intestinal tract, where they primarily inhabit the gut-associate lymphoid tissue (GALT), such as Peyer's patches and isolated lymphoid follicles. In addition to their role in taking up and presenting antigens, macrophages and DCs possess extensive functional plasticity and these cells play complementary roles in maintaining immune homeostasis in the gut by preventing aberrant immune responses to harmless antigens and microbes and by promoting host defense against pathogens. The ability of macrophages and DCs to induce either inflammation or tolerance is partially lineage imprinted, but can also be dictated by their activation state, which in turn is determined by their specific microenvironment. These cells express several surface and intracellular receptors that detect danger signals, nutrients, and hormones, which can affect their activation state. DCs and macrophages play a fundamental role in regulating T cells and their effector functions. Thus, modulation of intestinal mucosa immunity by targeting antigen presenting cells can provide a promising approach for controlling pathological inflammation. In this review, we provide an overview on the characteristics, functions, and origins of intestinal macrophages and DCs, highlighting the intestinal microenvironmental factors that influence their functions during homeostasis. Unraveling the mechanisms by which macrophages and DCs regulate intestinal immunity will deepen our understanding on how the immune system integrates endogenous and exogenous signals in order to maintain the host's homeostasis.
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Affiliation(s)
- Alessandra A Filardy
- Laboratório de Imunologia Celular, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Brazil.
| | - Jesuino R M Ferreira
- Laboratório de Imunologia Celular, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Brazil
| | - Rafael M Rezende
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, USA
| | - Brian L Kelsall
- Laboratory of Molecular Immunology, NIAID, National Institutes of Health, USA
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Zhu J, Wang Y, Li J, Das PK, Zhang H, Passang T, Li JM, Nagy T, Gandhi K, Ravindranathan S, Giver CR, Hassan M, Li Y, Antonova AU, Wang S, Roback JD, Waller EK. Donor plasmacytoid dendritic cells limit graft-versus-host disease through vasoactive intestinal polypeptide expression. Blood 2022; 140:1431-1447. [PMID: 35443019 PMCID: PMC9507007 DOI: 10.1182/blood.2021012561] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 03/21/2022] [Indexed: 11/20/2022] Open
Abstract
Vasoactive intestinal polypeptide (VIP), an anti-inflammatory neuropeptide with pleiotropic cardiovascular effects, induces differentiation of hematopoietic stem cells into regulatory dendritic cells that limit graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplant (HSCT) recipients. We have previously shown that donor plasmacytoid dendritic cells (pDCs) in bone marrow (BM) donor grafts limit the pathogenesis of GVHD. In this current study we show that murine and human pDCs express VIP, and that VIP-expressing pDCs limit T-cell activation and expansion using both in vivo and in vitro model systems. Using T cells or pDCs from transgenic luciferase+ donors in murine bone marrow transplantation (BMT), we show similar homing patterns of donor pDCs and T cells to the major sites for alloactivation of donor T cells: spleen and gut. Cotransplanting VIP-knockout (KO) pDCs with hematopoietic stem cells and T cells in major histocompatibility complex mismatched allogeneic BMT led to lower survival, higher GVHD scores, and more colon crypt cell apoptosis than transplanting wild-type pDCs. BMT recipients of VIP-KO pDCs had more T helper 1 polarized T cells, and higher plasma levels of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-α than recipients of wild-type pDCs. T cells from VIP-KO pDC recipients had increasing levels of bhlhe40 transcripts during the first 2 weeks posttransplant, and higher levels of CyclophilinA/Ppia transcripts at day 15 compared with T cells from recipients of wild-type pDCs. Collectively, these data indicate paracrine VIP synthesis by donor pDCs limits pathogenic T-cell inflammation, supporting a novel mechanism by which donor immune cells regulate T-cell activation and GVHD in allogeneic BMT.
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Affiliation(s)
- Jingru Zhu
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
- Department of Oncology, Xiangya Hospital, Central South University (CSU), Changsha, People's Republic of China
| | - Yitong Wang
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
- Department of Oncology, Xiangya Hospital, Central South University (CSU), Changsha, People's Republic of China
| | - Jingxia Li
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
- Department of Oncology, Xiangya Hospital, Central South University (CSU), Changsha, People's Republic of China
- Department of Hematology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Pankoj Kumar Das
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Hanwen Zhang
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Tenzin Passang
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Jian Ming Li
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Tamas Nagy
- Comparative Pathology Laboratory, Department of Pathology, College of Veterinary Medicine, University of Georgia, Atlanta, GA
| | - Khanjan Gandhi
- Bioinformatics & Systems Biology Shared Resource, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Sruthi Ravindranathan
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Cynthia R Giver
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | | | - Yiwen Li
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | | | - Shuhua Wang
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - John D Roback
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA
| | - Edmund K Waller
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
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Puri S, Kenyon BM, Hamrah P. Immunomodulatory Role of Neuropeptides in the Cornea. Biomedicines 2022; 10:1985. [PMID: 36009532 PMCID: PMC9406019 DOI: 10.3390/biomedicines10081985] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/11/2022] [Accepted: 08/12/2022] [Indexed: 12/21/2022] Open
Abstract
The transparency of the cornea along with its dense sensory innervation and resident leukocyte populations make it an ideal tissue to study interactions between the nervous and immune systems. The cornea is the most densely innervated tissue of the body and possesses both immune and vascular privilege, in part due to its unique repertoire of resident immune cells. Corneal nerves produce various neuropeptides that have a wide range of functions on immune cells. As research in this area expands, further insights are made into the role of neuropeptides and their immunomodulatory functions in the healthy and diseased cornea. Much remains to be known regarding the details of neuropeptide signaling and how it contributes to pathophysiology, which is likely due to complex interactions among neuropeptides, receptor isoform-specific signaling events, and the inflammatory microenvironment in disease. However, progress in this area has led to an increase in studies that have begun modulating neuropeptide activity for the treatment of corneal diseases with promising results, necessitating the need for a comprehensive review of the literature. This review focuses on the role of neuropeptides in maintaining the homeostasis of the ocular surface, alterations in disease settings, and the possible therapeutic potential of targeting these systems.
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Affiliation(s)
- Sudan Puri
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA
- Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA
| | - Brendan M. Kenyon
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA
- Program in Neuroscience, Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA
| | - Pedram Hamrah
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA
- Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA
- Program in Neuroscience, Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA
- Departments of Immunology and Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA
- Cornea Service, Tufts New England Eye Center, Boston, MA 02111, USA
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10
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Scheib N, Tiemann J, Becker C, Probst HC, Raker VK, Steinbrink K. The Dendritic Cell Dilemma in the Skin: Between Tolerance and Immunity. Front Immunol 2022; 13:929000. [PMID: 35837386 PMCID: PMC9275407 DOI: 10.3389/fimmu.2022.929000] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 05/30/2022] [Indexed: 11/17/2022] Open
Abstract
Dendritic cells (DC) are uniquely capable of initiating and directing immune responses. The range of their activities grounds in the heterogeneity of DC subsets and their functional plasticity. Numerical and functional DC changes influence the development and progression of disease, and correction of such dysregulations has the potential to treat disease causally. In this review, we discuss the major advances in our understanding of the regulation of DC lineage formation, differentiation, and function in the skin. We describe the alteration of DC in disease as well as possibilities for therapeutic reprogramming with a focus on tolerogenic DC. Because regulatory T cells (Treg) are indispensable partners of DC in the induction and control of tolerance, we pay special attention to the interactions with these cells. Above all, we would like to arouse fascination for this cell type and its therapeutic potential in skin diseases.
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Affiliation(s)
- Nils Scheib
- Department of Dermatology, University Hospital, Westfälische Wilhelms-University Münster, Münster, Germany
| | - Jessica Tiemann
- Department of Dermatology, University Hospital, Westfälische Wilhelms-University Münster, Münster, Germany
| | - Christian Becker
- Department of Dermatology, University Hospital, Westfälische Wilhelms-University Münster, Münster, Germany
| | - Hans Christian Probst
- Institute for Immunology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Verena Katharina Raker
- Department of Dermatology, University Hospital, Westfälische Wilhelms-University Münster, Münster, Germany
- *Correspondence: Verena Katharina Raker,
| | - Kerstin Steinbrink
- Department of Dermatology, University Hospital, Westfälische Wilhelms-University Münster, Münster, Germany
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11
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Tang R, Acharya N, Subramanian A, Purohit V, Tabaka M, Hou Y, He D, Dixon KO, Lambden C, Xia J, Rozenblatt-Rosen O, Sobel RA, Wang C, Regev A, Anderson AC, Kuchroo VK. Tim-3 adapter protein Bat3 acts as an endogenous regulator of tolerogenic dendritic cell function. Sci Immunol 2022; 7:eabm0631. [PMID: 35275752 PMCID: PMC9273260 DOI: 10.1126/sciimmunol.abm0631] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Dendritic cells (DCs) sense environmental cues and adopt either an immune-stimulatory or regulatory phenotype, thereby fine-tuning immune responses. Identifying endogenous regulators that determine DC function can thus inform the development of therapeutic strategies for modulating the immune response in different disease contexts. Tim-3 plays an important role in regulating immune responses by inhibiting the activation status and the T cell priming ability of DC in the setting of cancer. Bat3 is an adaptor protein that binds to the tail of Tim-3; therefore, we studied its role in regulating the functional status of DCs. In murine models of autoimmunity (experimental autoimmune encephalomyelitis) and cancer (MC38-OVA-implanted tumor), lack of Bat3 expression in DCs alters the T cell compartment-it decreases TH1, TH17 and cytotoxic effector cells, increases regulatory T cells, and exhausted CD8+ tumor-infiltrating lymphocytes, resulting in the attenuation of autoimmunity and acceleration of tumor growth. We found that Bat3 expression levels were differentially regulated by activating versus inhibitory stimuli in DCs, indicating a role for Bat3 in the functional calibration of DC phenotypes. Mechanistically, loss of Bat3 in DCs led to hyperactive unfolded protein response and redirected acetyl-coenzyme A to increase cell intrinsic steroidogenesis. The enhanced steroidogenesis in Bat3-deficient DC suppressed T cell response in a paracrine manner. Our findings identified Bat3 as an endogenous regulator of DC function, which has implications for DC-based immunotherapies.
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Affiliation(s)
- Ruihan Tang
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Nandini Acharya
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Ayshwarya Subramanian
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Vinee Purohit
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Marcin Tabaka
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Yu Hou
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Danyang He
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Karen O. Dixon
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Connor Lambden
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Junrong Xia
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | | | | | - Chao Wang
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Aviv Regev
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biology, Howard Hughes Medical Institute and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Ana C. Anderson
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Vijay K. Kuchroo
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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12
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Dawicki W, Huang H, Ma Y, Town J, Zhang X, Rudulier CD, Gordon JR. CD40 signaling augments IL-10 expression and the tolerogenicity of IL-10-induced regulatory dendritic cells. PLoS One 2021; 16:e0248290. [PMID: 33793599 PMCID: PMC8016274 DOI: 10.1371/journal.pone.0248290] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 02/23/2021] [Indexed: 11/23/2022] Open
Abstract
CD40 expressed on stimulatory dendritic cells (DC) provides an important accessory signal for induction of effector T cell responses. It is also expressed at lower levels on regulatory DC (DCreg), but there is little evidence that CD40 signaling contributes to the tolerogenic activity of these cells. Indeed, CD40 silencing within DCreg has been reported to induce T cell tolerance in multiple disease models, suggesting that CD40 is superfluous to DC-induced tolerance. We critically assessed whether CD40 does have a role in tolerance induced by IL-10-differentiated DC (DC10) by using DC10 generating from the bone marrow of wild-type (w.t.) or CD40-/- donor mice, or IL-10-complemented CD40-/- DC10 to treat asthmatic mice. Wild-type DC10 ablated the OVA-asthma phenotype via induction of Foxp3+ Treg responses, but CD40-/- DC10 had no discernible effects on primary facets of the phenotype (e.g., IL-5, IL-9, IL-13 levels, IgE & IgG1 antibodies; p>0.05) and were ≤40% effective in reversal of others. Foxp3+ T cells from the lungs of CD40-/- DC10-treated mice expressed reduced levels of a panel of six Treg-specific activation markers relative to Treg from w.t. DC10-treated mice. Coculture with effector T cells from asthmatic mice induced a marked upregulation of cell surface CD40 on w.t. DC10. While untreated CD40-/- and w.t. DC10 secreted equally low levels of IL-10, stimulation of w.t. DC10 with anti-CD40 for 72 h increased their expression of IL-10 by ≈250%, with no parallel induction of IL-12. Complementing IL-10 expression in CD40-/- DC10 by IL-10 mRNA transfection fully restored the cells’ abilities to suppress the asthma phenotype. In summary, CD40 signaling in DC10 contributes importantly to their expression of IL-10 and to a robust induction of tolerance, including activation of induced Treg.
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Affiliation(s)
- Wojciech Dawicki
- Department of Medicine, University of Saskatchewan, Saskatoon, Saskatoon, Canada
| | - Hui Huang
- Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Saskatoon, Canada
| | - Yanna Ma
- Department of Medicine, University of Saskatchewan, Saskatoon, Saskatoon, Canada
| | - Jennifer Town
- Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Saskatoon, Canada
| | - Xiaobei Zhang
- Department of Medicine, University of Saskatchewan, Saskatoon, Saskatoon, Canada
| | - Chris D. Rudulier
- Department of Medicine, University of Saskatchewan, Saskatoon, Saskatoon, Canada
| | - John R. Gordon
- Department of Medicine, University of Saskatchewan, Saskatoon, Saskatoon, Canada
- * E-mail:
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13
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Ness S, Lin S, Gordon JR. Regulatory Dendritic Cells, T Cell Tolerance, and Dendritic Cell Therapy for Immunologic Disease. Front Immunol 2021; 12:633436. [PMID: 33777019 PMCID: PMC7988082 DOI: 10.3389/fimmu.2021.633436] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 01/18/2021] [Indexed: 12/12/2022] Open
Abstract
Dendritic cells (DC) are antigen-presenting cells that can communicate with T cells both directly and indirectly, regulating our adaptive immune responses against environmental and self-antigens. Under some microenvironmental conditions DC develop into anti-inflammatory cells which can induce immunologic tolerance. A substantial body of literature has confirmed that in such settings regulatory DC (DCreg) induce T cell tolerance by suppression of effector T cells as well as by induction of regulatory T cells (Treg). Many in vitro studies have been undertaken with human DCreg which, as a surrogate marker of antigen-specific tolerogenic potential, only poorly activate allogeneic T cell responses. Fewer studies have addressed the abilities of, or mechanisms by which these human DCreg suppress autologous effector T cell responses and induce infectious tolerance-promoting Treg responses. Moreover, the agents and properties that render DC as tolerogenic are many and varied, as are the cells’ relative regulatory activities and mechanisms of action. Herein we review the most current human and, where gaps exist, murine DCreg literature that addresses the cellular and molecular biology of these cells. We also address the clinical relevance of human DCreg, highlighting the outcomes of pre-clinical mouse and non-human primate studies and early phase clinical trials that have been undertaken, as well as the impact of innate immune receptors and symbiotic microbial signaling on the immunobiology of DCreg.
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Affiliation(s)
- Sara Ness
- Department of Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Shiming Lin
- Department of Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - John R Gordon
- Department of Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.,Division of Respirology, Critical Care and Sleep Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
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14
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Iberg CA, Hawiger D. Natural and Induced Tolerogenic Dendritic Cells. THE JOURNAL OF IMMUNOLOGY 2020; 204:733-744. [PMID: 32015076 DOI: 10.4049/jimmunol.1901121] [Citation(s) in RCA: 169] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 10/04/2019] [Indexed: 11/19/2022]
Abstract
Dendritic cells (DCs) are highly susceptible to extrinsic signals that modify the functions of these crucial APCs. Maturation of DCs induced by diverse proinflammatory conditions promotes immune responses, but certain signals also induce tolerogenic functions in DCs. These "induced tolerogenic DCs" help to moderate immune responses such as those to commensals present at specific anatomical locations. However, also under steady-state conditions, some DCs are characterized by inherent tolerogenic properties. The immunomodulatory mechanisms constitutively present in such "natural tolerogenic DCs" help to promote tolerance to peripheral Ags. By extending tolerance initially established in the thymus, these functions of DCs help to regulate autoimmune and other immune responses. In this review we will discuss the mechanisms and functions of natural and induced tolerogenic DCs and offer further insight into how their possible manipulations may ultimately lead to more precise treatments for various immune-mediated conditions and diseases.
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Affiliation(s)
- Courtney A Iberg
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104
| | - Daniel Hawiger
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104
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15
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Machhi J, Kevadiya BD, Muhammad IK, Herskovitz J, Olson KE, Mosley RL, Gendelman HE. Harnessing regulatory T cell neuroprotective activities for treatment of neurodegenerative disorders. Mol Neurodegener 2020; 15:32. [PMID: 32503641 PMCID: PMC7275301 DOI: 10.1186/s13024-020-00375-7] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 04/13/2020] [Indexed: 02/07/2023] Open
Abstract
Emerging evidence demonstrates that adaptive immunity influences the pathobiology of neurodegenerative disorders. Misfolded aggregated self-proteins can break immune tolerance leading to the induction of autoreactive effector T cells (Teffs) with associated decreases in anti-inflammatory neuroprotective regulatory T cells (Tregs). An imbalance between Teffs and Tregs leads to microglial activation, inflammation and neuronal injury. The cascade of such a disordered immunity includes the drainage of the aggregated protein antigens into cervical lymph nodes serving to amplify effector immune responses. Both preclinical and clinical studies demonstrate transformation of this altered immunity for therapeutic gain. We posit that the signs and symptoms of common neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and stroke can be attenuated by boosting Treg activities.
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Affiliation(s)
- Jatin Machhi
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5880 USA
| | - Bhavesh D. Kevadiya
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5880 USA
- Department of Radiology, School of Medicine, Stanford University, Palo Alto, 94304 USA
| | - Ijaz Khan Muhammad
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5880 USA
- Department of Pharmacy, University of Swabi, Anbar Swabi, 23561 Pakistan
| | - Jonathan Herskovitz
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5880 USA
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-5880 USA
| | - Katherine E. Olson
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5880 USA
| | - R. Lee Mosley
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5880 USA
| | - Howard E. Gendelman
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5880 USA
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-5880 USA
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16
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Martínez C, Juarranz Y, Gutiérrez-Cañas I, Carrión M, Pérez-García S, Villanueva-Romero R, Castro D, Lamana A, Mellado M, González-Álvaro I, Gomariz RP. A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases. Int J Mol Sci 2019; 21:E65. [PMID: 31861827 PMCID: PMC6982157 DOI: 10.3390/ijms21010065] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 12/16/2019] [Accepted: 12/18/2019] [Indexed: 12/11/2022] Open
Abstract
The neuroendocrine and immune systems are coordinated to maintain the homeostasis of the organism, generating bidirectional communication through shared mediators and receptors. Vasoactive intestinal peptide (VIP) is the paradigm of an endogenous neuropeptide produced by neurons and endocrine and immune cells, involved in the control of both innate and adaptive immune responses. Exogenous administration of VIP exerts therapeutic effects in models of autoimmune/inflammatory diseases mediated by G-protein-coupled receptors (VPAC1 and VPAC2). Currently, there are no curative therapies for inflammatory and autoimmune diseases, and patients present complex diagnostic, therapeutic, and prognostic problems in daily clinical practice due to their heterogeneous nature. This review focuses on the biology of VIP and VIP receptor signaling, as well as its protective effects as an immunomodulatory factor. Recent progress in improving the stability, selectivity, and effectiveness of VIP/receptors analogues and new routes of administration are highlighted, as well as important advances in their use as biomarkers, contributing to their potential application in precision medicine. On the 50th anniversary of VIP's discovery, this review presents a spectrum of potential clinical benefits applied to inflammatory and autoimmune diseases.
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Affiliation(s)
- Carmen Martínez
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Yasmina Juarranz
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Irene Gutiérrez-Cañas
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Mar Carrión
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Selene Pérez-García
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Raúl Villanueva-Romero
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - David Castro
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Amalia Lamana
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Mario Mellado
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología (CNB)/CSIC, 28049 Madrid, Spain;
| | - Isidoro González-Álvaro
- Servicio de Reumatología, Instituto de Investigación Médica, Hospital Universitario La Princesa, 28006 Madrid, Spain;
| | - Rosa P. Gomariz
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
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17
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Castorina A, Vogiatzis M, Kang JWM, Keay KA. PACAP and VIP expression in the periaqueductal grey of the rat following sciatic nerve constriction injury. Neuropeptides 2019; 74:60-69. [PMID: 30579677 DOI: 10.1016/j.npep.2018.12.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 12/13/2018] [Accepted: 12/13/2018] [Indexed: 11/24/2022]
Abstract
Nerve injuries often result in neuropathic pain with co-morbid changes in social behaviours, motivation, sleep-wake cycles and neuroendocrine function. In an animal model of neuropathic injury (CCI) similar co-morbid changes are evoked in a subpopulation (~30%) of injured rats. In addition to anatomical evidence of altered neuronal and glial function, the periaqueductal grey (PAG) of these rats shows evidence of cell death. These changes in the PAG may play a role in the disruption of the normal emotional coping responses triggered by nerve injury. Cell death can occur via a number of mechanisms, including the disruption of neuroprotective mechanisms. Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two endogenous neuropeptides whose activities are tightly regulated by two receptors subtypes, namely the PAC1 and VPAC receptors. These peptides and their receptors exert robust neuroprotective roles. In these studies, we hypothesized that rats expressing disabilities following CCI showed altered expression of PACAP and VIP in the PAG. Rats were categorized as having either Pain alone, Transient or Persistent disability, based on changes in social behaviours pre- and post-CCI. Social interaction behavioural tested (BT), sham-injured and naïve untested rats were also included. For measurements of mRNA and protein expression we utilised micro-dissected PAGs blocks taken from each group. At the mRNA level, VIP was downregulated and PAC1 was upregulated in BT animals, whilst VPAC1 mRNA was specifically increased in the Pain alone group. Interestingly, protein levels of both PACAP and VIP were remarkably increased in the Persistent Disability group. Taken together, sciatic nerve CCI that triggers neuropathic pain and persistent disability results in abnormally increased VIP and PACAP expression in the PAG. Our data also suggest that these effects are likely to be governed by post-transcriptional mechanisms.
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Affiliation(s)
- Alessandro Castorina
- School of Medical Sciences (Anatomy and Histology), The University of Sydney, Sydney, NSW 2006, Australia.
| | - Monica Vogiatzis
- School of Medical Sciences (Anatomy and Histology), The University of Sydney, Sydney, NSW 2006, Australia
| | - James W M Kang
- School of Medical Sciences (Anatomy and Histology), The University of Sydney, Sydney, NSW 2006, Australia
| | - Kevin A Keay
- School of Medical Sciences (Anatomy and Histology), The University of Sydney, Sydney, NSW 2006, Australia
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18
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Schneider S, Wright CM, Heuckeroth RO. Unexpected Roles for the Second Brain: Enteric Nervous System as Master Regulator of Bowel Function. Annu Rev Physiol 2019; 81:235-259. [DOI: 10.1146/annurev-physiol-021317-121515] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
At the most fundamental level, the bowel facilitates absorption of small molecules, regulates fluid and electrolyte flux, and eliminates waste. To successfully coordinate this complex array of functions, the bowel relies on the enteric nervous system (ENS), an intricate network of more than 500 million neurons and supporting glia that are organized into distinct layers or plexi within the bowel wall. Neuron and glial diversity, as well as neurotransmitter and receptor expression in the ENS, resembles that of the central nervous system. The most carefully studied ENS functions include control of bowel motility, epithelial secretion, and blood flow, but the ENS also interacts with enteroendocrine cells, influences epithelial proliferation and repair, modulates the intestinal immune system, and mediates extrinsic nerve input. Here, we review the many different cell types that communicate with the ENS, integrating data about ENS function into a broader view of human health and disease. In particular, we focus on exciting new literature highlighting relationships between the ENS and its lesser-known interacting partners.
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Affiliation(s)
- Sabine Schneider
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Christina M. Wright
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Robert O. Heuckeroth
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Abramson Research Center, The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania 19104, USA
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19
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Guan L, Yu D, Wu GH, Ning HJ, He SD, Li SS, Hu TY, Yang G, Liu ZQ, Yu HQ, Sun XZ, Liu ZG, Yang PC. Vasoactive intestinal peptide is required in the maintenance of immune regulatory competency of immune regulatory monocytes. Clin Exp Immunol 2019; 196:276-286. [PMID: 30636174 DOI: 10.1111/cei.13259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/03/2019] [Indexed: 11/27/2022] Open
Abstract
Dysfunction of the immune regulatory system plays an important role in the pathogenesis of rheumatoid arthritis (RA). Vasoactive intestinal peptide (VIP) has multiple bioactivities. This study aims to investigate the role of VIP in the maintenance of the immune regulatory capacity of monocytes (Mos). Human peripheral blood samples were collected from RA patients and healthy control (HC) subjects. Mos and CD14+ CD71- CD73+ CD25+ regulatory Mos (RegMos) were isolated from the blood samples and characterized by flow cytometry. A rat RA model was developed to test the role of VIP in the maintenance of the immune regulatory function of Mos. The results showed that RegMos of HC subjects had immune suppressive functions. RegMos of RA patients expressed less interleukin (IL)-10 and showed an incompetent immune regulatory capacity. Serum levels of VIP were lower in RA patients, which were positively correlated with the expression of IL-10 in RegMos. In-vitro experiments showed that the IL-10 mRNA decayed spontaneously in RegMos, which could be prevented by the presence of VIP in the culture. VIP suppressed the effects of tristetraprolin (TTP) on inducing IL-10 mRNA decay in RegMos. Administration of VIP inhibited experimental RA in rats through restoring the IL-10 expression in RegMos. RegMos have immune suppressive functions. VIP is required in maintaining IL-10 expression in RegMos. The data suggest that VIP has translational potential in the treatment of immune disorders such as RA.
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Affiliation(s)
- L Guan
- Department of Respirology, Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - D Yu
- Research Center of Allergy and Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - G-H Wu
- Department of Respirology, Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - H-J Ning
- Research Center of Allergy and Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - S-D He
- Research Center of Allergy and Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - S-S Li
- Research Center of Allergy and Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - T-Y Hu
- Research Center of Allergy and Immunology, Shenzhen University School of Medicine, Shenzhen, China.,Longgang ENT Hospital and Shenzhen ENT Institute, Shenzhen, China
| | - G Yang
- Research Center of Allergy and Immunology, Shenzhen University School of Medicine, Shenzhen, China.,Longgang ENT Hospital and Shenzhen ENT Institute, Shenzhen, China
| | - Z-Q Liu
- Research Center of Allergy and Immunology, Shenzhen University School of Medicine, Shenzhen, China.,Longgang ENT Hospital and Shenzhen ENT Institute, Shenzhen, China
| | - H-Q Yu
- Department of Respirology, Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - X-Z Sun
- Department of Respirology, Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Z-G Liu
- Research Center of Allergy and Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - P-C Yang
- Research Center of Allergy and Immunology, Shenzhen University School of Medicine, Shenzhen, China
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20
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Abstract
The interplay between the immune and nervous systems has been acknowledged in the past, but only more recent studies have started to unravel the cellular and molecular players of such interactions. Mounting evidence indicates that environmental signals are sensed by discrete neuro-immune cell units (NICUs), which represent defined anatomical locations in which immune and neuronal cells colocalize and functionally interact to steer tissue physiology and protection. These units have now been described in multiple tissues throughout the body, including lymphoid organs, adipose tissue, and mucosal barriers. As such, NICUs are emerging as important orchestrators of multiple physiological processes, including hematopoiesis, organogenesis, inflammation, tissue repair, and thermogenesis. In this review we focus on the impact of NICUs in tissue physiology and how this fast-evolving field is driving a paradigm shift in our understanding of immunoregulation and organismal physiology.
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Affiliation(s)
- Cristina Godinho-Silva
- Champalimaud Research, Champalimaud Centre for the Unknown, 1400-038 Lisboa, Portugal; , ,
| | - Filipa Cardoso
- Champalimaud Research, Champalimaud Centre for the Unknown, 1400-038 Lisboa, Portugal; , ,
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21
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Švajger U, Rožman P. Induction of Tolerogenic Dendritic Cells by Endogenous Biomolecules: An Update. Front Immunol 2018; 9:2482. [PMID: 30416505 PMCID: PMC6212600 DOI: 10.3389/fimmu.2018.02482] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 10/08/2018] [Indexed: 12/19/2022] Open
Abstract
The importance of microenvironment on dendritic cell (DC) function and development has been strongly established during the last two decades. Although DCs with general tolerogenic characteristics have been isolated and defined as a particular sub-population, it is predominantly their unequivocal biological plasticity, which allows for unparalleled responsiveness to environmental ques and shaping of their tolerogenic characteristics when interacting with tolerance-inducing biomolecules. Dendritic cells carry receptors for a great number of endogenous factors, which, after ligation, can importantly influence the development of their activation state. For this there is ample evidence merely by observation of DC characteristics isolated from various anatomical niches, e.g., the greater immunosuppressive potential of DCs isolated from intestine compared to conventional blood DCs. Endogenous biomolecules present in these environments most likely play a major role as a determinant of their phenotype and function. In this review, we will concisely summarize in what way various, tolerance-inducing endogenous factors influence DC biology, the development of their particular tolerogenic state and their subsequent actions in context of immune response inhibition and induction of regulatory T cells.
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Affiliation(s)
- Urban Švajger
- Department for Therapeutic Services, Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia.,Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Primož Rožman
- Department for Therapeutic Services, Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia
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22
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Tasyurek HM, Eksi YE, Sanlioglu AD, Altunbas HA, Balci MK, Griffith TS, Sanlioglu S. HIV-based lentivirus-mediated vasoactive intestinal peptide gene delivery protects against DIO animal model of Type 2 diabetes. Gene Ther 2018; 25:269-283. [PMID: 29523882 DOI: 10.1038/s41434-018-0011-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 12/25/2017] [Accepted: 02/13/2018] [Indexed: 12/30/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is characterised by insulin resistance, glucose intolerance and beta cell loss leading to hyperglycemia. Vasoactive intestinal peptide (VIP) has been regarded as a novel therapeutic agent for the treatment of T2DM because of its insulinotropic and anti-inflammatory properties. Despite these beneficial properties, VIP is extremely sensitive to peptidases (DPP-4) requiring constant infusion or multiple injections to observe any therapeutic benefit. Thus, we constructed an HIV-based lentiviral vector encoding human VIP (LentiVIP) to test the therapeutic efficacy of VIP peptide in a diet-induced obesity (DIO) animal model of T2DM. VIP gene expression was shown by immunocytochemistry (ICC) and VIP peptide secretion was confirmed by ELISA both in HepG2 liver and MIN6 pancreatic beta cell lines. Functional properties of VIP were demonstrated by cAMP production assay and glucose-stimulated insulin secretion test (GSIS). Intraperitoneal (IP) delivery of LentiVIP vectors into mice significantly increased serum VIP concentrations compared to control mice. Most importantly, LentiVIP delivery in DIO animal model of T2DM resulted in improved insulin sensitivity, glucose tolerance and protection against STZ-induced diabetes in addition to reduction in serum triglyceride/cholesterol levels. Collectively, these data suggest LentiVIP delivery should be evaluated as an experimental therapeutic approach for the treatment of T2DM.
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Affiliation(s)
- Hale M Tasyurek
- Human Gene and Cell Therapy Center of Akdeniz University Hospitals, 07058, Antalya, Turkey
| | - Yunus E Eksi
- Human Gene and Cell Therapy Center of Akdeniz University Hospitals, 07058, Antalya, Turkey
| | - Ahter D Sanlioglu
- Human Gene and Cell Therapy Center of Akdeniz University Hospitals, 07058, Antalya, Turkey
| | - Hasan A Altunbas
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Akdeniz University Faculty of Medicine, 07058, Antalya, Turkey
| | - Mustafa K Balci
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Akdeniz University Faculty of Medicine, 07058, Antalya, Turkey
| | - Thomas S Griffith
- Department of Urology, University of Minnesota, School of Medicine, Minneapolis, MN, 55455, USA
| | - Salih Sanlioglu
- Human Gene and Cell Therapy Center of Akdeniz University Hospitals, 07058, Antalya, Turkey.
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23
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Domogalla MP, Rostan PV, Raker VK, Steinbrink K. Tolerance through Education: How Tolerogenic Dendritic Cells Shape Immunity. Front Immunol 2017; 8:1764. [PMID: 29375543 PMCID: PMC5770648 DOI: 10.3389/fimmu.2017.01764] [Citation(s) in RCA: 159] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 11/27/2017] [Indexed: 12/27/2022] Open
Abstract
Dendritic cells (DCs) are central players in the initiation and control of responses, regulating the balance between tolerance and immunity. Tolerogenic DCs are essential in the maintenance of central and peripheral tolerance by induction of clonal T cell deletion and T cell anergy, inhibition of memory and effector T cell responses, and generation and activation of regulatory T cells. Therefore, tolerogenic DCs are promising candidates for specific cellular therapy of allergic and autoimmune diseases and for treatment of transplant rejection. Studies performed in rodents have demonstrated the efficacy and feasibility of tolerogenic DCs for tolerance induction in various inflammatory diseases. In the last years, numerous protocols for the generation of human monocyte-derived tolerogenic DCs have been established and some first phase I trials have been conducted in patients suffering from autoimmune disorders, demonstrating the safety and efficiency of this cell-based immunotherapy. This review gives an overview about methods and protocols for the generation of human tolerogenic DCs and their mechanisms of tolerance induction with the focus on interleukin-10-modulated DCs. In addition, we will discuss the prerequisites for optimal clinical grade tolerogenic DC subsets and results of clinical trials with tolerogenic DCs in autoimmune diseases.
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Affiliation(s)
- Matthias P Domogalla
- Department of Dermatology, Division for Experimental and Translational Research, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.,Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Patricia V Rostan
- Department of Dermatology, Division for Experimental and Translational Research, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.,Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Verena K Raker
- Department of Dermatology, Division for Experimental and Translational Research, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.,Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Kerstin Steinbrink
- Department of Dermatology, Division for Experimental and Translational Research, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.,Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
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24
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Obregon C, Kumar R, Pascual MA, Vassalli G, Golshayan D. Update on Dendritic Cell-Induced Immunological and Clinical Tolerance. Front Immunol 2017; 8:1514. [PMID: 29250057 PMCID: PMC5715373 DOI: 10.3389/fimmu.2017.01514] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 10/26/2017] [Indexed: 12/18/2022] Open
Abstract
Dendritic cells (DCs) as highly efficient antigen-presenting cells are at the interface of innate and adaptive immunity. As such, they are key mediators of immunity and antigen-specific immune tolerance. Due to their functional specialization, research efforts have focused on the characterization of DCs subsets involved in the initiation of immunogenic responses and in the maintenance of tissue homeostasis. Tolerogenic DCs (tolDCs)-based therapies have been designed as promising strategies to prevent and control autoimmune diseases as well as allograft rejection after solid organ transplantation (SOT). Despite successful experimental studies and ongoing phase I/II clinical trials using autologous tolDCs in patients with type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and in SOT recipients, additional basic research will be required to determine the optimal DC subset(s) and conditioning regimens for tolDCs-based treatments in vivo. In this review, we discuss the characteristics of human DCs and recent advances in their classification, as well as the role of DCs in immune regulation and their susceptibility to in vitro or in vivo manipulation for the development of tolerogenic therapies, with a focus on the potential of tolDCs for the treatment of autoimmune diseases and the prevention of allograft rejection after SOT.
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Affiliation(s)
- Carolina Obregon
- Department of Medicine, Transplantation Centre and Transplantation Immunopathology Laboratory, Service of Immunology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Rajesh Kumar
- Department of Medicine, Transplantation Centre and Transplantation Immunopathology Laboratory, Service of Immunology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Manuel Antonio Pascual
- Department of Medicine, Transplantation Centre and Transplantation Immunopathology Laboratory, Service of Immunology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.,Department of Surgery, Transplantation Centre, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Giuseppe Vassalli
- Département coeur-vaisseaux, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.,Fondazione Cardiocentro Ticino, Swiss Institute of Regenerative Medicine (SIRM), Lugano, Switzerland
| | - Déla Golshayan
- Department of Medicine, Transplantation Centre and Transplantation Immunopathology Laboratory, Service of Immunology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.,Department of Surgery, Transplantation Centre, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
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25
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Obreque J, Vega F, Torres A, Cuitino L, Mackern-Oberti JP, Viviani P, Kalergis A, Llanos C. Autologous tolerogenic dendritic cells derived from monocytes of systemic lupus erythematosus patients and healthy donors show a stable and immunosuppressive phenotype. Immunology 2017; 152:648-659. [PMID: 28763099 DOI: 10.1111/imm.12806] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 06/23/2017] [Accepted: 07/20/2017] [Indexed: 12/20/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease with unrestrained T-cell and B-cell activity towards self-antigens. Evidence shows that apoptotic cells (ApoCells) trigger an autoreactive response against nuclear antigens in susceptible individuals. In this study, we focus on generating and characterizing tolerogenic dendritic cells (tolDCs) to restore tolerance to ApoCells. Monocyte-derived dendritic cells (DCs) from healthy controls and patients with SLE were treated with dexamethasone and rosiglitazone to induce tolDCs. Autologous apoptotic lymphocytes generated by UV irradiation were given to tolDCs as a source of self-antigens. Lipopolysaccharide (LPS) was used as a maturation stimulus to induce the expression of co-stimulatory molecules and secretion of cytokines. TolDCs generated from patients with SLE showed a reduced expression of co-stimulatory molecules after LPS stimulation compared with mature DCs. The same phenomenon was observed in tolDCs treated with ApoCells and LPS. In addition, ApoCell-loaded tolDCs stimulated with LPS secreted lower levels of interleukin-6 (IL-6) and IL-12p70 than mature DCs without differences in IL-10 secretion. The functionality of tolDCs was assessed by their capacity to prime allogeneic T cells. TolDCs displayed suppressor properties as demonstrated by a significantly reduced capacity to induce allogeneic T-cell proliferation and activation. ApoCell-loaded tolDCs generated from SLE monocytes have a stable immature/tolerogenic phenotype that can modulate CD4+ T-cell activation. These properties make them suitable for an antigen-specific immunotherapy for SLE.
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Affiliation(s)
- Javiera Obreque
- Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Fabián Vega
- Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Andy Torres
- Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Loreto Cuitino
- Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan P Mackern-Oberti
- Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), CONICET, Mendoza, Argentina.,Instituto de Fisiología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina
| | - Paola Viviani
- Departamento de Salud Pública, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alexis Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Endocrinología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Llanos
- Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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26
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Petersen CT, Li JM, Waller EK. Administration of a vasoactive intestinal peptide antagonist enhances the autologous anti-leukemia T cell response in murine models of acute leukemia. Oncoimmunology 2017. [PMID: 28638725 DOI: 10.1080/2162402x.2017.1304336] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Vasoactive intestinal peptide (VIP) is a neuroendocrine peptide hormone that has potent anti-inflammatory activities. VIP signaling through its receptor VPAC1 on T cells leads to reduced proliferation and a reduction in pro-inflammatory cytokine secretion. We report here that inhibition of the VIP pathway with a peptide antagonist significantly enhances a T-cell-dependent, autologous anti-leukemia response in murine models of acute myeloid leukemia and T lymphoblastic leukemia. Subcutaneous administration of the VIP antagonist, VIPhyb, resulted in reduced tumor burden and significantly enhanced survival (30-50% survival) over vehicle-treated controls (0-20% survival). The T cells in mice treated with VIPhyb expressed lower levels of the co-inhibitory PD-1 and secreted higher levels of IFNγ. Furthermore, T cells from VIPhyb-treated survivors were protective against C1498 following adoptive transfer. These data highlight the potential for the VIP pathway as a novel target for immunomodulation in settings of hematological malignancies.
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Affiliation(s)
- Christopher T Petersen
- Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - Jian-Ming Li
- Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - Edmund K Waller
- Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA, USA
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27
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Abstract
Dendritic cells (DCs) comprise heterogeneous subsets, functionally classified into conventional DCs (cDCs) and plasmacytoid DCs (pDCs). DCs are considered to be essential antigen (Ag)-presenting cells (APCs) that play crucial roles in activation and fine-tuning of innate and adaptive immunity under inflammatory conditions, as well as induction of immune tolerance to maintain immune homeostasis under steady-state conditions. Furthermore, DC functions can be modified and influenced by stimulation with various extrinsic factors, such as ligands for pattern-recognition receptors (PRRs) and cytokines. On the other hand, treatment of DCs with certain immunosuppressive drugs and molecules leads to the generation of tolerogenic DCs that show downregulation of both the major histocompatibility complex (MHC) and costimulatory molecules, and not only show defective T-cell activation, but also possess tolerogenic properties including the induction of anergic T-cells and regulatory T (Treg) cells. To develop an effective strategy for Ag-specific intervention of T-cell-mediated immune disorders, we have previously established the modified DCs with moderately high levels of MHC molecules that are defective in the expression of costimulatory molecules that had a greater immunoregulatory property than classical tolerogenic DCs, which we therefore designated as regulatory DCs (DCreg). Herein, we integrate the current understanding of the role of DCs in the control of immune responses, and further provide new information of the characteristics of tolerogenic DCs and DCreg, as well as their regulation of immune responses and disorders.
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Affiliation(s)
- Katsuaki Sato
- Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan. .,Japan Agency for Medical Research and Development (AMED), 1-7-1 Otemachi, Chiyoda-Ku, Tokyo, 100-0004, Japan.
| | - Tomofumi Uto
- Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.,Japan Agency for Medical Research and Development (AMED), 1-7-1 Otemachi, Chiyoda-Ku, Tokyo, 100-0004, Japan
| | - Tomohiro Fukaya
- Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.,Japan Agency for Medical Research and Development (AMED), 1-7-1 Otemachi, Chiyoda-Ku, Tokyo, 100-0004, Japan
| | - Hideaki Takagi
- Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.,Japan Agency for Medical Research and Development (AMED), 1-7-1 Otemachi, Chiyoda-Ku, Tokyo, 100-0004, Japan
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28
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Jung WC, Levesque JP, Ruitenberg MJ. It takes nerve to fight back: The significance of neural innervation of the bone marrow and spleen for immune function. Semin Cell Dev Biol 2017; 61:60-70. [DOI: 10.1016/j.semcdb.2016.08.010] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2016] [Revised: 08/09/2016] [Accepted: 08/11/2016] [Indexed: 01/17/2023]
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29
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Mashaghi A, Marmalidou A, Tehrani M, Grace PM, Pothoulakis C, Dana R. Neuropeptide substance P and the immune response. Cell Mol Life Sci 2016; 73:4249-4264. [PMID: 27314883 PMCID: PMC5056132 DOI: 10.1007/s00018-016-2293-z] [Citation(s) in RCA: 305] [Impact Index Per Article: 33.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 05/25/2016] [Accepted: 06/09/2016] [Indexed: 02/07/2023]
Abstract
Substance P is a peptide mainly secreted by neurons and is involved in many biological processes, including nociception and inflammation. Animal models have provided insights into the biology of this peptide and offered compelling evidence for the importance of substance P in cell-to-cell communication by either paracrine or endocrine signaling. Substance P mediates interactions between neurons and immune cells, with nerve-derived substance P modulating immune cell proliferation rates and cytokine production. Intriguingly, some immune cells have also been found to secrete substance P, which hints at an integral role of substance P in the immune response. These communications play important functional roles in immunity including mobilization, proliferation and modulation of the activity of immune cells. This review summarizes current knowledge of substance P and its receptors, as well as its physiological and pathological roles. We focus on recent developments in the immunobiology of substance P and discuss the clinical implications of its ability to modulate the immune response.
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Affiliation(s)
- Alireza Mashaghi
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114 USA
| | - Anna Marmalidou
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114 USA
| | - Mohsen Tehrani
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114 USA
| | - Peter M. Grace
- Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, CO 80309 USA
| | - Charalabos Pothoulakis
- Division of Digestive Diseases, David Geffen School of Medicine, Inflammatory Bowel Disease Center, University of California, Los Angeles, Los Angeles, CA USA
| | - Reza Dana
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114 USA
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30
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Abad C, Jayaram B, Becquet L, Wang Y, O’Dorisio MS, Waschek JA, Tan YV. VPAC1 receptor (Vipr1)-deficient mice exhibit ameliorated experimental autoimmune encephalomyelitis, with specific deficits in the effector stage. J Neuroinflammation 2016; 13:169. [PMID: 27357191 PMCID: PMC4928347 DOI: 10.1186/s12974-016-0626-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 06/14/2016] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase-activating polypeptide (PACAP) are two highly homologous neuropeptides. In vitro and ex vivo experiments repeatedly demonstrate that these peptides exert pronounced immunomodulatory (primarily anti-inflammatory) actions which are mediated by common VPAC1 and VPAC2 G protein-coupled receptors. In agreement, we have shown that mice deficient in PACAP ligand or VPAC2 receptors exhibit exacerbated experimental autoimmune encephalomyelitis (EAE). However, we observed that VIP-deficient mice are unexpectedly resistant to EAE, suggesting a requirement for this peptide at some stage of disease development. Here, we investigated the involvement of VPAC1 in the development of EAE using a VPAC1-deficient mouse model. METHODS EAE was induced in wild-type (WT) and VPAC1 knockout (KO) mice using myelin oligodendrocyte glycoprotein 35-55 (MOG35-55), and clinical scores were assessed continuously over 30 days. Immune responses in the spinal cords were determined by histology, real-time PCR and immunofluorescence, and in the draining lymph nodes by antigen-recall assays. The contribution of VPAC1 expression in the immune system to the development of EAE was evaluated by means of adoptive transfer and bone marrow chimera experiments. In other experiments, VPAC1 receptor analogs were given to WT mice. RESULTS MOG35-55-induced EAE was ameliorated in VPAC1 KO mice compared to WT mice. The EAE-resistant phenotype of VPAC1 KO mice correlated with reduced central nervous system (CNS) histopathology and cytokine expression in the spinal cord. The immunization phase of EAE appeared to be unimpaired because lymph node cells from EAE-induced VPAC1 KO mice stimulated in vitro with MOG exhibited robust proliferative and Th1/Th17 responses. Moreover, lymph node and spleen cells from KO mice were fully capable of inducing EAE upon transfer to WT recipients. In contrast, WT cells from MOG-immunized mice did not transfer the disease when administered to VPAC1 KO recipients, implicating a defect in the effector phase of the disease. Bone marrow chimera studies suggested that the resistance of VPAC1-deficient mice was only minimally dependent on the expression of this receptor in the immunogenic/hematopoietic compartment. Consistent with this, impaired spinal cord inductions of several chemokine mRNAs were observed in VPAC1 KO mice. Finally, treatment of WT mice with the VPAC1 receptor antagonist PG97-269 before, but not after, EAE induction mimicked the clinical phenotype of VPAC1 KO mice. CONCLUSIONS VPAC1 gene loss impairs the development of EAE in part by preventing an upregulation of CNS chemokines and invasion of inflammatory cells into the CNS. Use of VPAC1 antagonists in WT mice prior to EAE induction also support a critical role for VPAC1 signaling for the development of EAE.
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MESH Headings
- Adoptive Transfer
- Animals
- Central Nervous System/immunology
- Central Nervous System/metabolism
- Central Nervous System/pathology
- Cytokines/genetics
- Cytokines/metabolism
- Disease Models, Animal
- Encephalomyelitis, Autoimmune, Experimental/chemically induced
- Encephalomyelitis, Autoimmune, Experimental/complications
- Encephalomyelitis, Autoimmune, Experimental/genetics
- Female
- Freund's Adjuvant/toxicity
- Laminin/metabolism
- Lymph Nodes/pathology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Myelin-Oligodendrocyte Glycoprotein/toxicity
- Peptide Fragments/toxicity
- RNA, Messenger/metabolism
- Receptors, Vasoactive Intestinal Polypeptide, Type I/deficiency
- Receptors, Vasoactive Intestinal Polypeptide, Type I/genetics
- Spinal Cord/metabolism
- Spinal Cord/pathology
- Th1 Cells/metabolism
- Th1 Cells/pathology
- Th17 Cells/metabolism
- Th17 Cells/pathology
- Time Factors
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Affiliation(s)
- Catalina Abad
- />Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, USA
- />Inserm U905, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Normandy, France
| | - Bhavaani Jayaram
- />Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, USA
| | - Laurine Becquet
- />Inserm U905, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Normandy, France
| | - Yuki Wang
- />Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, USA
| | - M Sue O’Dorisio
- />Department of Pediatrics and Holden Comprehensive Cancer Center, RJ and LA Carver College of Medicine, University of Iowa, Iowa City, 52242 IA USA
| | - James A. Waschek
- />Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, USA
| | - Yossan-Var Tan
- />Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, USA
- />Inserm U905, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Normandy, France
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31
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Olivar R, Luque A, Cárdenas-Brito S, Naranjo-Gómez M, Blom AM, Borràs FE, Rodriguez de Córdoba S, Zipfel PF, Aran JM. The Complement Inhibitor Factor H Generates an Anti-Inflammatory and Tolerogenic State in Monocyte-Derived Dendritic Cells. THE JOURNAL OF IMMUNOLOGY 2016; 196:4274-90. [PMID: 27076676 DOI: 10.4049/jimmunol.1500455] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 02/27/2016] [Indexed: 12/14/2022]
Abstract
The activation of the complement system is a key initiating step in the protective innate immune-inflammatory response against injury, although it may also cause harm if left unchecked. The structurally related soluble complement inhibitors C4b-binding protein (C4BP) and factor H (FH) exert a tight regulation of the classical/lectin and alternative pathways of complement activation, respectively, attenuating the activity of the C3/C5 convertases and, consequently, avoiding serious damage to host tissues. We recently reported that the acute-phase C4BP isoform C4BP lacking the β-chain plays a pivotal role in the modulation of the adaptive immune responses. In this study, we demonstrate that FH acts in the early stages of monocyte to dendritic cell (DC) differentiation and is able to promote a distinctive tolerogenic and anti-inflammatory profile on monocyte-derived DCs (MoDCs) challenged by a proinflammatory stimulus. Accordingly, FH-treated and LPS-matured MoDCs are characterized by altered cytoarchitecture, resembling immature MoDCs, lower expression of the maturation marker CD83 and the costimulatory molecules CD40, CD80, and CD86, decreased production of key proinflammatory Th1-cytokines (IL-12, TNF-α, IFN-γ, IL-6, and IL-8), and preferential production of immunomodulatory mediators (IL-10 and TGF-β). Moreover, FH-treated MoDCs show low Ag uptake and, when challenged with LPS, display reduced CCR7 expression and chemotactic migration, impaired CD4(+) T cell alloproliferation, inhibition of IFN-γ secretion by the allostimulated T cells, and, conversely, induction of CD4(+)CD127(low/negative)CD25(high)Foxp3(+) regulatory T cells. Thus, this novel noncanonical role of FH as an immunological brake able to directly affect the function of MoDCs in an inflammatory environment may exhibit therapeutic potential in hypersensitivity, transplantation, and autoimmunity.
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Affiliation(s)
- Rut Olivar
- Human Molecular Genetics Group, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, 08908 Barcelona, Spain
| | - Ana Luque
- Human Molecular Genetics Group, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, 08908 Barcelona, Spain
| | - Sonia Cárdenas-Brito
- Human Molecular Genetics Group, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, 08908 Barcelona, Spain
| | - Mar Naranjo-Gómez
- Innovation in Vesicles and Cells for Application Therapy Group, Germans Trias i Pujol Health Sciences Research Institute, 08916 Badalona, Barcelona, Spain; Nephrology Service, Germans Trias i Pujol University Hospital, 08916 Badalona, Barcelona, Spain
| | - Anna M Blom
- Section of Medical Protein Chemistry, Department of Laboratory Medicine, Lund University, 20502 Malmö, Sweden
| | - Francesc E Borràs
- Innovation in Vesicles and Cells for Application Therapy Group, Germans Trias i Pujol Health Sciences Research Institute, 08916 Badalona, Barcelona, Spain; Nephrology Service, Germans Trias i Pujol University Hospital, 08916 Badalona, Barcelona, Spain
| | | | - Peter F Zipfel
- Department of Infection Biology, Leibniz Institute for Natural Products Research and Infection Biology, 07745 Jena, Germany
| | - Josep M Aran
- Human Molecular Genetics Group, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, 08908 Barcelona, Spain;
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32
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Xu Z, Ohtaki H, Watanabe J, Miyamoto K, Murai N, Sasaki S, Matsumoto M, Hashimoto H, Hiraizumi Y, Numazawa S, Shioda S. Pituitary adenylate cyclase-activating polypeptide (PACAP) contributes to the proliferation of hematopoietic progenitor cells in murine bone marrow via PACAP-specific receptor. Sci Rep 2016; 6:22373. [PMID: 26925806 PMCID: PMC4772629 DOI: 10.1038/srep22373] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 02/15/2016] [Indexed: 11/24/2022] Open
Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP, encoded by adcyap1) plays an important role in ectodermal development. However, the involvement of PACAP in the development of other germ layers is still unclear. This study assessed the expression of a PACAP-specific receptor (PAC1) gene and protein in mouse bone marrow (BM). Cells strongly expressing PAC1+ were large in size, had oval nuclei, and merged with CD34+ cells, suggesting that the former were hematopoietic progenitor cells (HPCs). Compared with wild-type mice, adcyap1−/− mice exhibited lower multiple potential progenitor cell populations and cell frequency in the S-phase of the cell cycle. Exogenous PACAP38 significantly increased the numbers of colony forming unit-granulocyte/macrophage progenitor cells (CFU-GM) with two peaks in semi-solid culture. PACAP also increased the expression of cyclinD1 and Ki67 mRNAs. These increases were completely and partially inhibited by the PACAP receptor antagonists, PACAP6-38 and VIP6-28, respectively. Little or no adcyap1 was expressed in BM and the number of CFU-GM colonies was similar in adcyap1−/− and wild-type mice. However, PACAP mRNA and protein were expressed in paravertebral sympathetic ganglia, which innervate tibial BM, and in the sympathetic fibers of BM cavity. These results suggested that sympathetic nerve innervation may be responsible for PACAP-regulated hematopoiesis in BM, mainly via PAC1.
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Affiliation(s)
- Zhifang Xu
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8555, Japan.,Division of Toxicology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8555, Japan.,Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Hirokazu Ohtaki
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8555, Japan
| | - Jun Watanabe
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8555, Japan.,Center for Biotechnology, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8555, Japan
| | - Kazuyuki Miyamoto
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8555, Japan
| | - Norimitsu Murai
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8555, Japan
| | - Shun Sasaki
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8555, Japan
| | - Minako Matsumoto
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8555, Japan
| | - Hitoshi Hashimoto
- Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Yutaka Hiraizumi
- Department of Orthopaedic Surgery, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8555, Japan
| | - Satoshi Numazawa
- Division of Toxicology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8555, Japan
| | - Seiji Shioda
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8555, Japan.,Peptide Drug Innovation, Global Research Center for Innovative Life Science, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan
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Delgado M. Immunobiology of the Pituitary Adenylate Cyclase-Activating Peptide. CURRENT TOPICS IN NEUROTOXICITY 2016:691-708. [DOI: 10.1007/978-3-319-35135-3_40] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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Di Giovangiulio M, Verheijden S, Bosmans G, Stakenborg N, Boeckxstaens GE, Matteoli G. The Neuromodulation of the Intestinal Immune System and Its Relevance in Inflammatory Bowel Disease. Front Immunol 2015; 6:590. [PMID: 26635804 PMCID: PMC4653294 DOI: 10.3389/fimmu.2015.00590] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 11/03/2015] [Indexed: 12/18/2022] Open
Abstract
One of the main tasks of the immune system is to discriminate and appropriately react to “danger” or “non-danger” signals. This is crucial in the gastrointestinal tract, where the immune system is confronted with a myriad of food antigens and symbiotic microflora that are in constant contact with the mucosa, in addition to any potential pathogens. This large number of antigens and commensal microflora, which are essential for providing vital nutrients, must be tolerated by the intestinal immune system to prevent aberrant inflammation. Hence, the balance between immune activation versus tolerance should be tightly regulated to maintain intestinal homeostasis and to prevent immune activation indiscriminately against all luminal antigens. Loss of this delicate equilibrium can lead to chronic activation of the intestinal immune response resulting in intestinal disorders, such as inflammatory bowel diseases (IBD). In order to maintain homeostasis, the immune system has evolved diverse regulatory strategies including additional non-immunological actors able to control the immune response. Accumulating evidence strongly indicates a bidirectional link between the two systems in which the brain modulates the immune response via the detection of circulating cytokines and via direct afferent input from sensory fibers and from enteric neurons. In the current review, we will highlight the most recent findings regarding the cross-talk between the nervous system and the mucosal immune system and will discuss the potential use of these neuronal circuits and neuromediators as novel therapeutic tools to reestablish immune tolerance and treat intestinal chronic inflammation.
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Affiliation(s)
- Martina Di Giovangiulio
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven , Leuven , Belgium
| | - Simon Verheijden
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven , Leuven , Belgium
| | - Goele Bosmans
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven , Leuven , Belgium
| | - Nathalie Stakenborg
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven , Leuven , Belgium
| | - Guy E Boeckxstaens
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven , Leuven , Belgium
| | - Gianluca Matteoli
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven , Leuven , Belgium
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Gao P, Gao XI, Fu T, Xu D, Wen Q. Acupuncture: Emerging evidence for its use as an analgesic (Review). Exp Ther Med 2015; 9:1577-1581. [PMID: 26136861 DOI: 10.3892/etm.2015.2348] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Accepted: 02/18/2015] [Indexed: 12/17/2022] Open
Abstract
Acupuncture is an ancient Chinese technique, developed over >3,000 years, in which 'acupoints' are stimulated with the aim of treating various diseases. A number of previous studies have indicated that acupuncture may play a role in inducing analgesia. Acupuncture-induced analgesia has been hypothesized to act on various parts of the central nervous system, including the spinal cord, brain stem, cerebral ganglia and cerebral cortex. The mechanisms underlying the effects of acupuncture have been purported to include neurohumors and neurotransmitters, such as opioids and γ-aminobutyric acid, signaling pathways and the immune response, which are all involved in the induction of analgesia.
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Affiliation(s)
- Peng Gao
- Department of Anesthesiology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - X I Gao
- Department of Anesthesiology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Tairan Fu
- Department of Anesthesiology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Dan Xu
- Department of Anesthesiology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Qingping Wen
- Department of Anesthesiology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
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Tan YV, Abad C, Wang Y, Lopez R, Waschek J. VPAC2 (vasoactive intestinal peptide receptor type 2) receptor deficient mice develop exacerbated experimental autoimmune encephalomyelitis with increased Th1/Th17 and reduced Th2/Treg responses. Brain Behav Immun 2015; 44:167-175. [PMID: 25305591 PMCID: PMC4275378 DOI: 10.1016/j.bbi.2014.09.020] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 09/23/2014] [Accepted: 09/25/2014] [Indexed: 01/01/2023] Open
Abstract
Vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase-activating polypeptide (PACAP) are two structurally-related neuropeptides with widespread expression in the central and peripheral nervous systems. Although these peptides have been repeatedly shown to exert potent anti-inflammatory actions when administered in animal models of inflammatory disease, mice deficient in VIP and PACAP were recently shown to exhibit different phenotypes (ameliorated and exacerbated, respectively) in response to experimental autoimmune encephalomyelitis (EAE). Therefore, elucidating what are the specific immunoregulatory roles played by each of their receptor subtypes (VPAC1, VPAC2, and PAC1) is critical. In this study, we found that mice with a genetic deletion of VIPR2, encoding the VPAC2 receptor, exhibited exacerbated (MOG35-55)-induced EAE compared to wild type mice, characterized by enhanced clinical and histopathological features, increased proinflammatory cytokines (TNF-α, IL-6, IFN-γ (Th1), and IL-17 (Th17)) and reduced anti-inflammatory cytokines (IL-10, TGFβ, and IL-4 (Th2)) in the CNS and lymph nodes. Moreover, the abundance and proliferative index of lymph node, thymus and CNS CD4(+)CD25(+)FoxP3(+) Tregs were strikingly reduced in VPAC2-deficient mice with EAE. Finally, the in vitro suppressive activity of lymph node and splenic Tregs from VPAC2-deficient mice was impaired. Overall, our results demonstrate critical protective roles for PACAP and the VPAC2 receptor against autoimmunity, promoting the expansion and maintenance of the Treg pool.
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Affiliation(s)
| | | | | | | | - James Waschek
- Corresponding author: James A. Waschek, Ph.D. 635 Charles E Young Drive South Los Angeles CA 90095 Phone number (310)-825-0179 FAX (310)-206-5061
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Luo Y, Cai X, Liu S, Wang S, Nold-Petry CA, Nold MF, Bufler P, Norris D, Dinarello CA, Fujita M. Suppression of antigen-specific adaptive immunity by IL-37 via induction of tolerogenic dendritic cells. Proc Natl Acad Sci U S A 2014; 111:15178-83. [PMID: 25294929 PMCID: PMC4210310 DOI: 10.1073/pnas.1416714111] [Citation(s) in RCA: 140] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
IL-1 family member IL-37 limits innate inflammation in models of colitis and LPS-induced shock, but a role in adaptive immunity remains unknown. Here, we studied mice expressing human IL-37b isoform (IL-37tg) subjected to skin contact hypersensitivity (CHS) to dinitrofluorobenzene. CHS challenge to the hapten was significantly decreased in IL-37tg mice compared with wild-type (WT) mice (-61%; P < 0.001 at 48 h). Skin dendritic cells (DCs) were present and migrated to lymph nodes after antigen uptake in IL-37tg mice. When hapten-sensitized DCs were adoptively transferred to WT mice, antigen challenge was greatly impaired in mice receiving DCs from IL-37tg mice compared with those receiving DCs from WT mice (-60%; P < 0.01 at 48 h). In DCs isolated from IL-37tg mice, LPS-induced increase of MHC II and costimulatory molecule CD40 was reduced by 51 and 31%, respectively. In these DCs, release of IL-1β, IL-6, and IL-12 was reduced whereas IL-10 secretion increased (37%). Consistent with these findings, DCs from IL-37tg mice exhibited a lower ability to stimulate syngeneic and allogeneic naive T cells as well as antigen-specific T cells and displayed enhanced induction of T regulatory (Treg) cells (86%; P < 0.001) in vitro. Histological analysis of CHS skin in mice receiving hapten-sensitized DCs from IL-37tg mice revealed a marked reduction in CD8(+) T cells (-74%) but an increase in Treg cells (2.6-fold). Together, these findings reveal that DCs expressing IL-37 are tolerogenic, thereby impairing activation of effector T-cell responses and inducing Treg cells. IL-37 thus emerges as an inhibitor of adaptive immunity.
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Affiliation(s)
| | - Xiangna Cai
- Departments of Dermatology and Department of Plastic and Reconstruct Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou City 515041, People's Republic of China
| | | | - Sen Wang
- Departments of Dermatology and Department of Plastic and Reconstruct Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou City 515041, People's Republic of China
| | - Claudia A Nold-Petry
- The Ritchie Centre, Monash Institute of Medical Research, Monash University, Melbourne, VIC 3800, Australia
| | - Marcel F Nold
- The Ritchie Centre, Monash Institute of Medical Research, Monash University, Melbourne, VIC 3800, Australia
| | - Philip Bufler
- Children's Hospital, Ludwig-Maximilians University, 80539 Munich, Germany; and
| | - David Norris
- Departments of Dermatology and Denver Veterans Affairs Medical Center, Denver, CO 80220
| | | | - Mayumi Fujita
- Departments of Dermatology and Denver Veterans Affairs Medical Center, Denver, CO 80220
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Filippini P, Rutella S. Recent advances on cellular therapies and immune modulators for graft-versus-host disease. Expert Rev Clin Immunol 2014; 10:1357-74. [PMID: 25196777 DOI: 10.1586/1744666x.2014.955475] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The efficacy of allogeneic hematopoietic stem cell transplantation is counterbalanced by the occurrence of life-threatening immune-mediated complications, such as graft-versus-host disease (GVHD), a multistep disease which is reportedly fatal to approximately 15% of transplant recipients. It is now established that T-cell-dendritic cell interactions, T-cell activation, release of proinflammatory cytokines and T-cell trafficking partake in GVHD pathogenesis. This article will focus on the most recent strategies aimed at preventing/treating GVHD by manipulating components of the innate and adaptive immune response from both the donor and the host.
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Affiliation(s)
- Perla Filippini
- Department of Systems Medicine, IRCCS San Raffaele Pisana, Rome, Italy
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Gordon JR, Ma Y, Churchman L, Gordon SA, Dawicki W. Regulatory dendritic cells for immunotherapy in immunologic diseases. Front Immunol 2014; 5:7. [PMID: 24550907 PMCID: PMC3907717 DOI: 10.3389/fimmu.2014.00007] [Citation(s) in RCA: 132] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Accepted: 01/07/2014] [Indexed: 12/12/2022] Open
Abstract
We recognize well the abilities of dendritic cells to activate effector T cell (Teff cell) responses to an array of antigens and think of these cells in this context as pre-eminent antigen-presenting cells, but dendritic cells are also critical to the induction of immunologic tolerance. Herein, we review our knowledge on the different kinds of tolerogenic or regulatory dendritic cells that are present or can be induced in experimental settings and humans, how they operate, and the diseases in which they are effective, from allergic to autoimmune diseases and transplant tolerance. The primary conclusions that arise from these cumulative studies clearly indicate that the agent(s) used to induce the tolerogenic phenotype and the status of the dendritic cell at the time of induction influence not only the phenotype of the dendritic cell, but also that of the regulatory T cell responses that they in turn mobilize. For example, while many, if not most, types of induced regulatory dendritic cells lead CD4+ naïve or Teff cells to adopt a CD25+Foxp3+ Treg phenotype, exposure of Langerhans cells or dermal dendritic cells to vitamin D leads in one case to the downstream induction of CD25+Foxp3+ regulatory T cell responses, while in the other to Foxp3− type 1 regulatory T cells (Tr1) responses. Similarly, exposure of human immature versus semi-mature dendritic cells to IL-10 leads to distinct regulatory T cell outcomes. Thus, it should be possible to shape our dendritic cell immunotherapy approaches for selective induction of different types of T cell tolerance or to simultaneously induce multiple types of regulatory T cell responses. This may prove to be an important option as we target diseases in different anatomic compartments or with divergent pathologies in the clinic. Finally, we provide an overview of the use and potential use of these cells clinically, highlighting their potential as tools in an array of settings.
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Affiliation(s)
- John R Gordon
- Department of Medicine, University of Saskatchewan , Saskatoon, SK , Canada
| | - Yanna Ma
- Department of Medicine, University of Saskatchewan , Saskatoon, SK , Canada
| | - Laura Churchman
- Department of Medicine, University of Saskatchewan , Saskatoon, SK , Canada
| | - Sara A Gordon
- Department of Medicine, University of Saskatchewan , Saskatoon, SK , Canada
| | - Wojciech Dawicki
- Department of Medicine, University of Saskatchewan , Saskatoon, SK , Canada
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Abstract
In recent years, there have been many new developments in the field of regulatory T cells (Treg), challenging the consensus on their behaviour, classification and role(s) in disease. The role Treg might play in autoimmune disease appears to be more complex than previously thought. Here, we discuss the current knowledge of regulatory T cells through animal and human research and illustrate the recent developments in childhood autoimmune arthritis (juvenile idiopathic arthritis (JIA)). Furthermore, this review summarises our understanding of the fields and assesses current and future implications for Treg in the treatment of JIA.
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Tuna H, Avdiushko RG, Sindhava VJ, Wedlund L, Kaetzel CS, Kaplan AM, Bondada S, Cohen DA. Regulation of the mucosal phenotype in dendritic cells by PPARγ: role of tissue microenvironment. J Leukoc Biol 2013; 95:471-85. [PMID: 24295831 DOI: 10.1189/jlb.0713408] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Mucosal DCs play a critical role in tissue homeostasis. Several stimuli can induce a mucosal phenotype; however, molecular pathways that regulate development of mucosal DC function are relatively unknown. This study sought to determine whether PPARγ contributes to the development of the "mucosal" phenotype in mouse DCs. Experiments demonstrated that PPARγ activation in BMDCs induced an immunosuppressive phenotype in which BMDCs had reduced expression of MHC class II and costimulatory molecules, increased IL-10 secretion, and reduced the ability to induce CD4 T cell proliferation. Activation of PPARγ enhanced the ability of BMDC to polarize CD4 T cells toward iTregs and to induce T cell expression of the mucosal homing receptor, CCR9. Activation of PPARγ increased the ability of BMDCs to induce T cell-independent IgA production in B cells. BMDCs from PPARγ(ΔDC) mice displayed enhanced expression of costimulatory molecules, enhanced proinflammatory cytokine production, and decreased IL-10 synthesis. Contrary to the inflammatory BMDC phenotype in vitro, PPARγ(ΔDC) mice showed no change in the frequency or phenotype of mDC in the colon. In contrast, mDCs in the lungs were increased significantly in PPARγ(ΔDC) mice. A modest increase in colitis severity was observed in DSS-treated PPARγ(ΔDC) mice compared with control. These results indicate that PPARγ activation induces a mucosal phenotype in mDCs and that loss of PPARγ promotes an inflammatory phenotype. However, the intestinal microenvironment in vivo can maintain the mucosal DC phenotype of via PPARγ-independent mechanisms.
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Affiliation(s)
- Halide Tuna
- 1.Immunology and Molecular Genetics, University of Kentucky, 800 Rose St., Room MS419, Lexington, KY 40536-0298, USA.
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Massoud AH, Yona M, Xue D, Chouiali F, Alturaihi H, Ablona A, Mourad W, Piccirillo CA, Mazer BD. Dendritic cell immunoreceptor: a novel receptor for intravenous immunoglobulin mediates induction of regulatory T cells. J Allergy Clin Immunol 2013; 133:853-63.e5. [PMID: 24210883 DOI: 10.1016/j.jaci.2013.09.029] [Citation(s) in RCA: 126] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Revised: 08/02/2013] [Accepted: 09/06/2013] [Indexed: 02/02/2023]
Abstract
BACKGROUND Intravenous immunoglobulin (IVIg) is a polyclonal IgG preparation with potent immunomodulating properties. Our laboratory demonstrated that IVIg significantly increases numbers of forkhead box protein 3-positive regulatory T (Treg) cells through generation of tolerogenic dendritic cells (DCs) in an allergic airways disease model. OBJECTIVE We sought to investigate potential receptors on DCs mediating these events. METHODS C57BL/6 mice were either sensitized to ovalbumin (OVA) intraperitoneally or through adoptive transfer of OVA-primed DCs and then challenged with intranasal OVA. IVIg was fractionated into sialic acid-enriched IVIg (SA-IVIg) and sialic acid-depleted IVIg (non-SA-IVIg). Dendritic cell immunoreceptor (DCIR) constructs in CHO cells or on DCs were examined by using fluorescent microscopy and flow cytometry. RESULTS Administration of SA-IVIg, but not non-SA-IVIg, to OVA-sensitized and OVA-challenged mice induced Treg cells and attenuated airway hyperresponsiveness (AHR) and inflammation comparably with IVIg. Bone marrow-derived dendritic cells cultured with SA-IVIg or IVIg adoptively transferred to mice before OVA challenge induced Treg cells and inhibited AHR. IVIg-treated bone marrow-derived dendritic cells from Fcγ receptor knockout mice inhibited AHR, suggesting IVIg's action was not caused by Fcγ receptor-mediated events. Fluorescently labeled IVIg or SA-IVIg bound DCs and colocalized specifically to the C-type lectin DCIR. IVIg binding to DCIR induced phosphorylation of Src homology domain 2-containing protein tyrosine phosphatase (SHP) 2 and Src homology domain 2-containing inositol phosphatase 1 (SHIP-1) and internalization of IVIg into DCs. Inhibition of IVIg binding to DCIR by small interfering RNA completely blocked induction of Treg cells. Inhibition of SHP-2 or abrogation of IgG internalization through clatherin inhibitors rendered IVIg ineffective. CONCLUSIONS IVIg alleviates allergic airways disease through interaction of SA-IgG with DCIR. DCIR is a novel receptor for IVIg, mediating interaction of innate and adaptive immunity in tolerogenic responses.
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Affiliation(s)
- Amir H Massoud
- Meakins Christie Laboratories, the Department of Pediatrics, Division of Allergy and Immunology, The Research Institute of the McGill University Health Center, and the Department of Medicine, McGill University, Montreal, Quebec, Canada; Département d'Immunologie et Microbiologie, Université de Montréal, Institute de Recherche du l'Hôpitale St-Luc, Montreal, Quebec, Canada
| | - Madelaine Yona
- Meakins Christie Laboratories, the Department of Pediatrics, Division of Allergy and Immunology, The Research Institute of the McGill University Health Center, and the Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Di Xue
- Meakins Christie Laboratories, the Department of Pediatrics, Division of Allergy and Immunology, The Research Institute of the McGill University Health Center, and the Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Fazila Chouiali
- Meakins Christie Laboratories, the Department of Pediatrics, Division of Allergy and Immunology, The Research Institute of the McGill University Health Center, and the Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Haydar Alturaihi
- Département d'Immunologie et Microbiologie, Université de Montréal, Institute de Recherche du l'Hôpitale St-Luc, Montreal, Quebec, Canada
| | - Aidan Ablona
- Meakins Christie Laboratories, the Department of Pediatrics, Division of Allergy and Immunology, The Research Institute of the McGill University Health Center, and the Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Walid Mourad
- Département d'Immunologie et Microbiologie, Université de Montréal, Institute de Recherche du l'Hôpitale St-Luc, Montreal, Quebec, Canada
| | - Ciriaco A Piccirillo
- Department of Microbiology and Immunology, The Research Institute of the McGill University Health Center, McGill University, Montreal, Quebec, Canada
| | - Bruce D Mazer
- Meakins Christie Laboratories, the Department of Pediatrics, Division of Allergy and Immunology, The Research Institute of the McGill University Health Center, and the Department of Medicine, McGill University, Montreal, Quebec, Canada.
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Matsumoto T, Hasegawa H, Onishi S, Ishizaki J, Suemori K, Yasukawa M. Protein kinase C inhibitor generates stable human tolerogenic dendritic cells. THE JOURNAL OF IMMUNOLOGY 2013; 191:2247-57. [PMID: 23878315 DOI: 10.4049/jimmunol.1203053] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Tolerogenic dendritic cells (DCs) are a promising tool for a specific form of cellular therapy whereby immunological tolerance can be induced in the context of transplantation and autoimmunity. From libraries of bioactive lipids, nuclear receptor ligands, and kinase inhibitors, we screened conventional protein kinase C inhibitors (PKCIs) bisindolylmaleimide I, Gö6983, and Ro32-0432 with strong tolerogenic potential. PKCI-treated human DCs were generated by subjecting them to a maturation process after differentiation of immature DCs. The PKCI-treated DCs had a semimature phenotype, showing high production of IL-10, and efficiently induced IL-10-producing T cells and functional Foxp3(+) regulatory T cells from naive CD4(+) T cells, thus eliciting a strong immunosuppressive function. They also showed CCR7 expression and sufficient capacity for migration toward CCR7 ligands. Additionally, PKCI-treated DCs were highly stable when exposed to inflammatory stimuli such as proinflammatory cytokines or LPS. Conventional PKCIs inhibited NF-κB activation of both the canonical and noncanonical pathways of DC maturation, thus suppressing the expression of costimulatory molecules and IL-12 production. High production of IL-10 in PKCI-treated DCs was due to not only an increase of intracellular cAMP, but also a synergistic effect of increased cAMP and NF-κB inhibition. Moreover, PKCI-treated mouse DCs that had properties similar to PKCI-treated human DCs prevented graft-versus-host disease in a murine model of acute graft-versus-host disease. Conventional PKCI-treated DCs may be useful for tolerance-inducing therapy, as they satisfy the required functional characteristics for clinical-grade tolerogenic DCs.
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Affiliation(s)
- Takuya Matsumoto
- Department of Bioregulatory Medicine, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
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Zhang A, Fu J, Ning B, Li D, Sun N, Wei W, Wei J, Ju X. Tolerogenic dendritic cells generated with IL-10/TGFβ1 relieve immune thrombocytopenia in mice. Thromb Res 2013; 132:63-8. [DOI: 10.1016/j.thromres.2013.04.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Revised: 03/02/2013] [Accepted: 04/01/2013] [Indexed: 01/22/2023]
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Chandrasekharan B, Nezami BG, Srinivasan S. Emerging neuropeptide targets in inflammation: NPY and VIP. Am J Physiol Gastrointest Liver Physiol 2013; 304:G949-57. [PMID: 23538492 PMCID: PMC3680683 DOI: 10.1152/ajpgi.00493.2012] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The enteric nervous system (ENS), referred to as the "second brain," comprises a vast number of neurons that form an elegant network throughout the gastrointestinal tract. Neuropeptides produced by the ENS play a crucial role in the regulation of inflammatory processes via cross talk with the enteric immune system. In addition, neuropeptides have paracrine effects on epithelial secretion, thus regulating epithelial barrier functions and thereby susceptibility to inflammation. Ultimately the inflammatory response damages the enteric neurons themselves, resulting in deregulations in circuitry and gut motility. In this review, we have emphasized the concept of neurogenic inflammation and the interaction between the enteric immune system and enteric nervous system, focusing on neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP). The alterations in the expression of NPY and VIP in inflammation and their significant roles in immunomodulation are discussed. We highlight the mechanism of action of these neuropeptides on immune cells, focusing on the key receptors as well as the intracellular signaling pathways that are activated to regulate the release of cytokines. In addition, we also examine the direct and indirect mechanisms of neuropeptide regulation of epithelial tight junctions and permeability, which are a crucial determinant of susceptibility to inflammation. Finally, we also discuss the potential of emerging neuropeptide-based therapies that utilize peptide agonists, antagonists, siRNA, oligonucleotides, and lentiviral vectors.
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Affiliation(s)
- Bindu Chandrasekharan
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
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Dendritic cells: cellular mediators for immunological tolerance. Clin Dev Immunol 2013; 2013:972865. [PMID: 23762100 PMCID: PMC3671285 DOI: 10.1155/2013/972865] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Accepted: 04/07/2013] [Indexed: 01/07/2023]
Abstract
In general, immunological tolerance is acquired upon treatment with non-specific immunosuppressive drugs. This indiscriminate immunosuppression of the patient often causes serious side-effects, such as opportunistic infectious diseases. Therefore, the need for antigen-specific modulation of pathogenic immune responses is of crucial importance in the treatment of inflammatory diseases. In this perspective, dendritic cells (DCs) can have an important immune-regulatory function, besides their notorious antigen-presenting capacity. DCs appear to be essential for both central and peripheral tolerance. In the thymus, DCs are involved in clonal deletion of autoreactive immature T cells by presenting self-antigens. Additionally, tolerance is achieved by their interactions with T cells in the periphery and subsequent induction of T cell anergy, T cell deletion, and induction of regulatory T cells (Treg). Various studies have described, modulation of DC characteristics with the purpose to induce antigen-specific tolerance in autoimmune diseases, graft-versus-host-disease (GVHD), and transplantations. Promising results in animal models have prompted researchers to initiate first-in-men clinical trials. The purpose of current review is to provide an overview of the role of DCs in the immunopathogenesis of autoimmunity, as well as recent concepts of dendritic cell-based therapeutic opportunities in autoimmune diseases.
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Horch M, Nguyen VH. Regulatory T-cell immunotherapy for allogeneic hematopoietic stem-cell transplantation. Ther Adv Hematol 2013; 3:29-44. [PMID: 23556110 DOI: 10.1177/2040620711422266] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
From mouse studies to recently published clinical trials, evidence has accumulated on the potential use of regulatory T cells (Treg) in preventing and treating graft-versus-host disease following hematopoietic-cell transplantation (HCT). However, controversies remain as to the phenotype and stability of various Treg subsets and their respective roles in vivo, the requirement of antigen-specificity of Treg to reduce promiscuous suppression, and the molecular mechanisms by which Treg suppress, particularly in humans. In this review, we discuss recent findings that support a heterogeneous population of human Treg, address advances in understanding how Treg function in the context of HCT, and present data on recent clinical trials that highlight the feasibility and limitations on Treg immunotherapy for graft-versus-host disease.
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Reichstetter S, Castillo GM, Rubinstein I, Nishimoto-Ashfield A, Lai M, Jones CC, Banerjee AA, Banjeree A, Lyubimov A, Bloedow DC, Bogdanov A, Bolotin EM. Protected graft copolymer excipient leads to a higher acute maximum tolerated dose and extends residence time of vasoactive intestinal Peptide significantly better than sterically stabilized micelles. Pharm Res 2013; 30:670-82. [PMID: 23224976 PMCID: PMC3734960 DOI: 10.1007/s11095-012-0904-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Accepted: 10/08/2012] [Indexed: 10/27/2022]
Abstract
PURPOSE To determine and compare pharmacokinetics and toxicity of two nanoformulations of Vasoactive Intestinal Peptide (VIP). METHODS VIP was formulated using a micellar (Sterically Stabilized Micelles, SSM) and a polymer-based (Protected Graft Copolymer, PGC) nanocarrier at various loading percentages. VIP binding to the nanocarriers, pharmacokinetics, blood pressure, blood chemistry, and acute maximum tolerated dose (MTD) of the formulations after injection into BALB/c mice were determined. RESULTS Both formulations significantly extend in vivo residence time compared to unformulated VIP. Formulation toxicity is dependent on loading percentage, showing major differences between the two carrier types. Both formulations increase in vivo potency of unformulated VIP and show acute MTDs at least 140 times lower than unformulated VIP, but still at least 100 times higher than the anticipated highest human dose, 1-5 μg/kg. These nanocarriers prevented a significant drop in arterial blood pressure compared to unformulated VIP. CONCLUSIONS While both carriers enhance in vivo residence time compared to unformulated VIP and reduce the drop in blood pressure immediately after injection, PGC is the excipient of choice to extend residence time and improve the safety of potent therapeutic peptides such as VIP.
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Olivar R, Luque A, Naranjo-Gómez M, Quer J, García de Frutos P, Borràs FE, Rodríguez de Córdoba S, Blom AM, Aran JM. The α7β0 isoform of the complement regulator C4b-binding protein induces a semimature, anti-inflammatory state in dendritic cells. THE JOURNAL OF IMMUNOLOGY 2013; 190:2857-72. [PMID: 23390292 DOI: 10.4049/jimmunol.1200503] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The classical pathway complement regulator C4b-binding protein (C4BP) is composed of two polypeptides (α- and β-chains), which form three plasma oligomers with different subunit compositions (α7β1, α7β0, and α6β1). We show in this article that the C4BP α7β0 isoform (hereafter called C4BP[β(-)] [C4BP lacking the β-chain]), overexpressed under acute-phase conditions, induces a semimature, tolerogenic state on human monocyte-derived dendritic cells (DCs) activated by a proinflammatory stimulus. C4BP isoforms containing β-chain (α7β1 and α6β1; C4BP[β(+)]) neither interfered with the normal maturation of DCs nor competed with C4BP(β(-)) activity on these cells. Immature DCs (iDCs) treated with C4BP(β(-)) retained high endocytic activity, but, upon LPS treatment, they did not upregulate surface expression of CD83, CD80, and CD86. Transcriptional profiling of these semimature DCs revealed that treatment with C4BP(β(-)) prevented the induction of IDO and BIC-1, whereas TGF-β1 expression was maintained to the level of iDCs. C4BP(β(-))-treated DCs were also unable to release proinflammatory Th1 cytokines (IL-12, TNF-α, IFN-γ, IL-6, IL-8) and, conversely, increased IL-10 secretion. They prevented surface CCR7 overexpression and, accordingly, displayed reduced chemotaxis, being morphologically indistinguishable from iDCs. Moreover, C4BP(β(-))-treated DCs failed to enhance allogeneic T cell proliferation, impairing IFN-γ production in these cells and, conversely, promoting CD4(+)CD127(low/neg)CD25(high)Foxp3(+) T cells. Deletion mutant analysis revealed that the complement control protein-6 domain of the α-chain is necessary for the tolerogenic activity of C4BP(β(-)). Our data demonstrate a novel anti-inflammatory and immunomodulatory function of the complement regulator C4BP, suggesting a relevant role of the acute-phase C4BP(β(-)) isoform in a number of pathophysiological conditions and potential applications in autoimmunity and transplantation.
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Affiliation(s)
- Rut Olivar
- Human Molecular Genetics Group, Bellvitge Biomedical Research Institute, 08908 L'Hospitalet de Llobregat, Barcelona, Spain
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Pharmacological inhibition of VIP signaling enhances antiviral immunity and improves survival in murine cytomegalovirus-infected allogeneic bone marrow transplant recipients. Blood 2013; 121:2347-51. [PMID: 23325838 DOI: 10.1182/blood-2012-06-437640] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Cytomegalovirus (CMV) infection following allogeneic bone marrow transplant (allo-BMT) is controlled by donor-derived cellular immunity. Vasoactive intestinal peptide (VIP) suppresses Th1 immunity. We hypothesized that blocking VIP-signaling would enhance anti-CMV immunity in murine recipients of allo-BMT. Recipients were transplanted with bone marrow (BM) and T-cells from major histocompatibility complex (MHC)-mismatched VIP-knockout (KO) or wild-type donors, and treated with 7 daily subcutaneous injections of VIPhyb (peptidic VIP-antagonist) or phosphate-buffered saline (PBS). Genetic and pharmacological blockade of VIP-signaling protected allo-BMT recipients from lethal murine CMV (mCMV) infection, improving survival without increasing graft-versus-host disease. Mice treated with VIPhyb or transplanted with VIP-KO allografts had significantly lower viral loads, increased numbers of mCMV-M45-peptide-MHC-tetramer(+) CD8(+) T-cells, with lower PD-1 expression, and enhanced primary and secondary cellular immune responses after mCMV infection than did PBS-treated mice. These results demonstrate that administration of a VIP antagonist after allo-BMT is a promising safely therapeutic approach to enhance antiviral cellular immunity.
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