Amiram Ariel | University of Haifa (original) (raw)
Papers by Amiram Ariel
Frontiers in Immunology
Editorial on the Research Topic Molecular and Cellular Effectors in the Resolution of Inflammatio... more Editorial on the Research Topic Molecular and Cellular Effectors in the Resolution of Inflammation Acute inflammation is broadly defined as a protective response of the organism to invading pathogens and tissue injury. The reaction should ideally be localized and self-limited, enabling the elimination of pathogens and damaged cells, and resolve on its own, leading to tissue repair and restoration of normal tissue and organ function (1). Uncontrolled or excessive inflammation or failure of the initial response to resolve in a timely manner leads to nonresolving inflammation, which is often chronic, or transient and relapsing (2). This ongoing low-grade inflammation is thought to fail to activate the integrated process of resolution (3), which is increasingly being recognized as a critical component of numerous prevalent human diseases, including atherosclerosis, arthritis, pulmonary diseases, autoimmunity, diabetes and cancer (2, 4). The inflammatory response is a complex process, heterogeneous in nature and depends on the type of disease and organ in which it occurs. The sequence of events and signaling circuits activated during the initiation and resolution phase have received considerable attention, and are summarized in guiding maps for inflammation (5) and resolution pathways (6). Resolution is an active process governed by endogenous resolution programs driven by specialized pro-resolving mediators (SPMs) acting at pro-resolving receptors (7). As an example, lipoxins synthesized from arachidonic acid during the resolution of self-limited inflammation function as stop signals through the receptor ALX/FPR2 for neutrophil recruitment, facilitate neutrophil apoptosis and efferocytosis (4), pivotal events in efficient resolution. Given the dual nature of inflammation and the importance of the inflammatory response in survival, it is paramount to develop new treatments to overcome the limitations of currently available antiinflammatory therapies, which are often accompanied with unwanted side effects and do not lead to repair of the affected tissues. Indeed, over the past few years a new branch of pharmacology termed "resolution pharmacology" (8, 9) has emerged, with the goal of developing strategies that promote resolution instead of blocking or inhibiting a mediator or pathway. This Research Topic brings together thirty-two articles, both reviews and original research papers, which highlight recent advances in resolution biology, wound repair, metabolic disorders, and acquired immunity using a large variety of experimental models. Twenty-four articles report
Frontiers in Pharmacology
Zoledronic acid (Zol) is a potent bisphosphonate that inhibits the differentiation of monocytes i... more Zoledronic acid (Zol) is a potent bisphosphonate that inhibits the differentiation of monocytes into osteoclasts. It is often used in combination with dexamethasone (Dex), a glucocorticoid that promotes the resolution of inflammation, to treat malignant diseases, such as multiple myeloma. This treatment can result in bone pathologies, namely medication related osteonecrosis of the jaw, with a poor understanding of the molecular mechanism on monocyte differentiation. IFN-β is a pro-resolving cytokine well-known as an osteoclast differentiation inhibitor. Here, we explored whether Zol and/or Dex regulate macrophage osteoclastic differentiation via IFN-β. RAW 264.7 and peritoneal macrophages were treated with Zol and/or Dex for 4–24 h, and IFN-β secretion was examined by ELISA, while the IFN stimulated gene (ISG) 15 expression was evaluated by Western blotting. RANKL-induced osteoclastogenesis of RAW 264.7 cells was determined by TRAP staining following treatment with Zol+Dex or IFN-β ...
Frontiers in Immunology
The resolution of inflammation is a temporally and spatially coordinated process that in its inna... more The resolution of inflammation is a temporally and spatially coordinated process that in its innate manifestations, primarily involves neutrophils and macrophages. The shutdown of infection or injury-induced acute inflammation requires termination of neutrophil accumulation within the affected sites, neutrophil demise, and clearance by phagocytes (efferocytosis), such as tissue-resident and monocyte-derived macrophages. This must be followed by macrophage reprogramming from the inflammatory to reparative and consequently resolution-promoting phenotypes and the production of resolution-promoting lipid and protein mediators that limit responses in various cell types and promote tissue repair and return to homeostatic architecture and function. Recent studies suggest that these events, and macrophage reprogramming to pro-resolving phenotypes in particular, are not only important in the acute setting, but might be paramount in limiting chronic inflammation, autoimmunity, and various unc...
Clinical Nutrition, 2021
BACKGROUND & AIMS Enteral nutrition (EN) and parenteral nutrition (PN) enriched with omega-3 ... more BACKGROUND & AIMS Enteral nutrition (EN) and parenteral nutrition (PN) enriched with omega-3 polyunsaturated fatty acids (PUFA) have beneficial effects in critical illness. This study aimed to assess the combined effect of EN and supplemental PN enriched with omega-3 PUFA on blood oxygenation in intensive care unit (ICU) patients. METHODS Single-center, prospective, randomized, controlled, double-blind, phase III trial conducted from 10/2013 to 11/2017. A total of 100 ICU patients (18-85 years, APACHE II score > 15) requiring mechanical ventilation were randomly assigned to received combined EN and PN either with omega-3 PUFA (omega-3 group) or without (control group) for up to 28 days. Primary endpoint: 'change of PaO2/FiO2 from day (D) 1 to D4'. Secondary endpoints: lung function parameters, ICU complications, length of hospital stay, days free of ICU care/ventilation/sedation/catecholamine treatment, mortality, erythrocyte fatty acid composition, inflammatory parameters. Safety parameters: standard laboratory assessment, vital signs, physical examination, SOFA score, adverse events. RESULTS Combined EN and PN covered energy requirements to more than 80%. Blood oxygenation (ΔPaO2/FiO2 from D1 to D4: -1.3 ± 83.7, n = 42, and 13.3 ± 86.1, n = 39, in omega-3 and control group, respectively, p = 0.7795) and other lung function parameters did not differ between groups but days free of catecholamine treatment were significantly higher in the omega-3 group (~4 days, p = 0.0481). On D6, significantly more patients in the omega-3 group tolerated EN alone (51.0% vs. 29.8%, p = 0.0342). Eicosapentaenoic acid (EPA) content in erythrocytes was significantly increased in the omega-3 group at last observation compared with the control group (ΔEPA: 0.928 ± 0.808% vs. -0.024 ± 0.190%, p < 0.0001). No further significant group differences were detected. CONCLUSIONS Enteral and supplemental PN both enriched with omega-3 PUFA did not improve lung function but allowed earlier weaning from catecholamine treatment and PN. Supplemental PN succeeded to adequately cover energy requirements in critically ill patients. TRIAL REGISTRATION www.clinicaltrials.gov, registration number: NCT01162928.
Frontiers in Immunology, Oct 2, 2018
Prostaglandins, Leukotrienes and Essential Fatty Acids, 2016
Pain is a complex sensation that may be protective or cause undue suffering and loss of function,... more Pain is a complex sensation that may be protective or cause undue suffering and loss of function, depending on the circumstances. Peripheral nociceptor neurons (PNs) innervate most tissues, and express ion channels, nocisensors, which depolarize the cell in response to intense stimuli and numerous substances. Inflamed tissues manifest inflammatory hyperalgesia in which the threshold for pain and the response to painful stimuli are decreased and increased, respectively. Constituents of the inflammatory milieu sensitize PNs, thereby contributing to hyperalgesia. Polyunsaturated fatty acids undergo enzymatic and free radical-mediated oxygenation into an array of bioactive metabolites, oxygenated polyunsaturated fatty acids (oxy-PUFAs), including the classic eicosanoids. Oxy-PUFA production is enhanced during inflammation. Pioneering studies by Vane and colleagues from the early 1970s first implicated classic eicosanoids in the pain associated with inflammation. Here, we review the production and action of oxy-PUFAs that are not classic eicosanoids, but nevertheless are produced in injured/ inflamed tissues and activate or sensitize PNs. In general, oxy-PUFAs that sensitize PNs may do so directly, by activation of nocisensors, ion channels or GPCRs expressed on the surface of PNs, or indirectly, by increasing the production of inflammatory mediators that activate or sensitize PNs. We focus on oxy-PUFAs that act directly on PNs. Specifically, we discuss the role of arachidonic acid-derived 12S-HpETE, HNE, ONE, PGA2, iso-PGA2 and 15d-PGJ2, 5,6-and 8,9-EET, PGE2-G and 8R,15S-diHETE, as well as the linoleic acid-derived 9-and 13-HODE in inducing acute nocifensive behavior and/or inflammatory hyperalgesia in rodents. The nocisensors TRPV1, TRPV4 and TRPA1, and putative Gαs-type GPCRs are the PN targets of these oxy-PUFAs.
The Journal of Immunology, May 1, 2013
Journal of Clinical Investigation, 2015
Frontiers Research Topics, 2013
The Journal of Immunology, 2001
European Journal of Immunology, 2010
European Journal of Immunology, 1997
The putative effects of interleukin (IL)-7, operating in the context of extracellular matrix (ECM... more The putative effects of interleukin (IL)-7, operating in the context of extracellular matrix (ECM), on the adhesion of human T cells were examined. Recombinant human, IL-7 was found to bind ECM or fibronectin (FN) with IC50 values of 10-100 nM. Nanogram amounts of both soluble and, especially, FN- or ECM-bound IL-7, which differentially affected the morphologies of FN-adherent T cells, induced the adhesion of resting CD4+ and CD8+ T cells in dose-dependent and beta 1 integrin-dependent manners. Under static and flow conditions, soluble IL-7 also induced the binding of unstimulated T cells to vascular cell adhesion molecule-1, suggesting that this cytokine can also modulate integrin binding to endothelial cell ligands. The effects of affinity modulation by IL-7 of FN-specific beta 1 integrins depend on the presence of soluble FN, which inhibited T cell adhesion to FN induced by FN-bound IL-7 or by an integrin-specific affinity-modulating monoclonal antibody, but not by soluble IL-7 or phorbol 12-myristate 13-acetate. These findings provide an example of a major ECM integrin ligand, FN, which is capable of modulating its adhesive interactions with specific immune cells by associating with and presenting a cytokine in a bio-active state.
European Journal of Clinical Investigation, 2018
Neutrophils are critically involved in host defence and they also modulate the inflammatory proce... more Neutrophils are critically involved in host defence and they also modulate the inflammatory process. Turning the inflammatory response towards a resolutive outcome requires a dialogue between apoptotic neutrophils and proresolving macrophages through complex key molecular interactions controlling efferocytosis, anti-inflammatory reprogramming and ultimately immune regulation. In this review, we will first focus on recent molecular analyses aiming at characterizing the role of proteins expressed on apoptotic neutrophils and their cognate partners expressed on macrophages in the resolution of inflammation. These will include chemokine receptors and their ligands and annexin A1 and its receptor FPR2. We will next depict how the structural and enzymatic properties of proteinase 3 (PR3), the autoantigen in vasculitis, allow its expression on apoptotic neutrophils, which in turn affects efferocytosis and immune response associated with the clearance of apoptotic cells. This example illustrates that the fate of apoptotic neutrophils directly influences the resolution of inflammation and immune responses thereby potentially contributing to systemic and nonresolving inflammation as well as autoimmunity.
The FASEB Journal, 2021
The resolution of inflammation facilitates proper wound healing and limits tissue repair short of... more The resolution of inflammation facilitates proper wound healing and limits tissue repair short of exaggerated fibrotic scarring. The atypical chemokine receptor (ACKR)2/D6 scavenges inflammatory chemokines, while IFN‐β is a recently unveiled pro‐resolving cytokine. Both effector molecules limit acute inflammatory episodes and promote their resolution in various organs. Here, we found fibrotic skin lesions from ACKR2−/− mice presented increased epidermal and dermal thickening, atrophy of the subcutaneous adipose tissue, augmented disorientation of collagen deposition, and enhanced deformation and loss of hair follicles compared to WT counterparts. In addition, affected skin sections from ACKR2−/− mice contained reduced levels of the pro‐resolving mediators IFN‐β and IL‐10, but increased levels of the pro‐inflammatory chemokines CCL2 and 3, the pro‐fibrotic cytokine TGF‐β, and the immune‐stimulating cytokine IL‐12. Notably, treatment with exogenous IFN‐β rescued, at least in part, all the pro‐fibrotic outcomes and lesion size in ACKR2−/− mice and promoted expression of the pro‐resolving enzyme 12/15‐lipoxygenase (LO) in both ACKR2−/− and WT mice. Moreover, Ifnb−/− mice displayed enhanced pro‐fibrotic indices upon exposure to bleomycin. These findings suggest ACKR2 is an important mediator in limiting inflammatory skin fibrosis and acts via IFN‐β production to promote the resolution of inflammation and minimize tissue scaring.
American Journal of Physiology-Cell Physiology, 2020
Neutrophils are polymorphonuclear leukocytes that play a central role in host defense against inf... more Neutrophils are polymorphonuclear leukocytes that play a central role in host defense against infection and tissue injury. They are rapidly recruited to the inflamed site and execute a variety of functions to clear invading pathogens and damaged cells. However, many of their defense mechanisms are capable of inflicting collateral tissue damage. Neutrophil-driven inflammation is a unifying mechanism underlying many common diseases. Efficient removal of neutrophils from inflammatory loci is critical for timely resolution of inflammation and return to homeostasis. Accumulating evidence challenges the classical view that neutrophils represent a homogeneous population and that halting neutrophil influx is sufficient to explain their rapid decline within inflamed loci during the resolution of protective inflammation. Hence, understanding the mechanisms that govern neutrophil functions and their removal from the inflammatory locus is critical for minimizing damage to the surrounding tissue...
Blood
Innate immune neutrophils provide the first line of host defense against bacterial infections. Ne... more Innate immune neutrophils provide the first line of host defense against bacterial infections. Neutrophils under steady state rely almost entirely on glycolysis and exhibit very low levels of oxidative phosphorylation. The metabolite lactate has long been considered a "waste byproduct" of cell metabolism which accumulates during inflammation and sepsis. Increased plasma lactate levels in human patients is used as a marker for sepsis diagnosis. However, the direct effector actions of lactate, particularly in regulating neutrophil mobilization and function during inflammation has remained obscure. To better understand the metabolic consequences of BM neutrophil activation during the onset of inflammation, we tested how bacterial lipopolysaccharides (mimicking gram negative bacterial inflammation) introduced intraperitoneally (i.p.) affect neutrophil metabolism and mobilization. RNAseq of sorted BM neutrophils revealed that LPS-activated neutrophils upregulate enzymes catalyz...
Apoptosis
ARTS (Sept4_i2) is a pro-apoptotic protein and a product of the Sept4 gene. ARTS acts upstream of... more ARTS (Sept4_i2) is a pro-apoptotic protein and a product of the Sept4 gene. ARTS acts upstream of mitochondria to initiate caspase activation. ARTS induces apoptosis by specifically binding XIAP and allowing de-repression of active caspases required for Mitochondrial Outer Membrane Permeabilzation (MOMP). Moreover, ARTS promotes apoptosis by inducing ubiquitin-mediated degradation of both major anti-apoptotic proteins XIAP and Bcl-2. In the resolution phase of inflammation, the infiltrating leukocytes, which execute the acute innate response, undergo apoptosis and are subsequently cleared by phagocytic macrophages (i.e . efferocytosis). In this course, macrophages undergo reprogramming from inflammatory, to anti-inflammatory, and eventually to resolving macrophages that leave the injury sites. Since engulfment of apoptotic leukocytes is a key signaling step in macrophage reprogramming and resolution of inflammation, we hypothesized that a failed apoptosis in leukocytes in vivo would result in an impaired resolution process. To test this hypothesis, we utilized the Sept4/ARTS −/− mice, which exhibit resistance to apoptosis in many cell types. During zymosan A-induced peritonitis, Sept4/ARTS −/− mice exhibited impaired resolution of inflammation, characterized by reduced neutrophil apoptosis, macrophage efferocytosis and expression of pro-resolving mediators. This was associated with increased pro-inflammatory cytokines and reduced anti-inflammatory cytokines, secreted by resolution-phase macrophages. Moreover, ARTS overexpression in leukocytes in vitro promoted an anti-inflammatory behavior. Overall, our results suggest that ARTS is a key master-regulator necessary for neutrophil apoptosis, macrophage efferocytosis and reprogramming to the pro-resolving phenotype during the resolution of inflammation.
Frontiers in Immunology
Editorial on the Research Topic Molecular and Cellular Effectors in the Resolution of Inflammatio... more Editorial on the Research Topic Molecular and Cellular Effectors in the Resolution of Inflammation Acute inflammation is broadly defined as a protective response of the organism to invading pathogens and tissue injury. The reaction should ideally be localized and self-limited, enabling the elimination of pathogens and damaged cells, and resolve on its own, leading to tissue repair and restoration of normal tissue and organ function (1). Uncontrolled or excessive inflammation or failure of the initial response to resolve in a timely manner leads to nonresolving inflammation, which is often chronic, or transient and relapsing (2). This ongoing low-grade inflammation is thought to fail to activate the integrated process of resolution (3), which is increasingly being recognized as a critical component of numerous prevalent human diseases, including atherosclerosis, arthritis, pulmonary diseases, autoimmunity, diabetes and cancer (2, 4). The inflammatory response is a complex process, heterogeneous in nature and depends on the type of disease and organ in which it occurs. The sequence of events and signaling circuits activated during the initiation and resolution phase have received considerable attention, and are summarized in guiding maps for inflammation (5) and resolution pathways (6). Resolution is an active process governed by endogenous resolution programs driven by specialized pro-resolving mediators (SPMs) acting at pro-resolving receptors (7). As an example, lipoxins synthesized from arachidonic acid during the resolution of self-limited inflammation function as stop signals through the receptor ALX/FPR2 for neutrophil recruitment, facilitate neutrophil apoptosis and efferocytosis (4), pivotal events in efficient resolution. Given the dual nature of inflammation and the importance of the inflammatory response in survival, it is paramount to develop new treatments to overcome the limitations of currently available antiinflammatory therapies, which are often accompanied with unwanted side effects and do not lead to repair of the affected tissues. Indeed, over the past few years a new branch of pharmacology termed "resolution pharmacology" (8, 9) has emerged, with the goal of developing strategies that promote resolution instead of blocking or inhibiting a mediator or pathway. This Research Topic brings together thirty-two articles, both reviews and original research papers, which highlight recent advances in resolution biology, wound repair, metabolic disorders, and acquired immunity using a large variety of experimental models. Twenty-four articles report
Frontiers in Pharmacology
Zoledronic acid (Zol) is a potent bisphosphonate that inhibits the differentiation of monocytes i... more Zoledronic acid (Zol) is a potent bisphosphonate that inhibits the differentiation of monocytes into osteoclasts. It is often used in combination with dexamethasone (Dex), a glucocorticoid that promotes the resolution of inflammation, to treat malignant diseases, such as multiple myeloma. This treatment can result in bone pathologies, namely medication related osteonecrosis of the jaw, with a poor understanding of the molecular mechanism on monocyte differentiation. IFN-β is a pro-resolving cytokine well-known as an osteoclast differentiation inhibitor. Here, we explored whether Zol and/or Dex regulate macrophage osteoclastic differentiation via IFN-β. RAW 264.7 and peritoneal macrophages were treated with Zol and/or Dex for 4–24 h, and IFN-β secretion was examined by ELISA, while the IFN stimulated gene (ISG) 15 expression was evaluated by Western blotting. RANKL-induced osteoclastogenesis of RAW 264.7 cells was determined by TRAP staining following treatment with Zol+Dex or IFN-β ...
Frontiers in Immunology
The resolution of inflammation is a temporally and spatially coordinated process that in its inna... more The resolution of inflammation is a temporally and spatially coordinated process that in its innate manifestations, primarily involves neutrophils and macrophages. The shutdown of infection or injury-induced acute inflammation requires termination of neutrophil accumulation within the affected sites, neutrophil demise, and clearance by phagocytes (efferocytosis), such as tissue-resident and monocyte-derived macrophages. This must be followed by macrophage reprogramming from the inflammatory to reparative and consequently resolution-promoting phenotypes and the production of resolution-promoting lipid and protein mediators that limit responses in various cell types and promote tissue repair and return to homeostatic architecture and function. Recent studies suggest that these events, and macrophage reprogramming to pro-resolving phenotypes in particular, are not only important in the acute setting, but might be paramount in limiting chronic inflammation, autoimmunity, and various unc...
Clinical Nutrition, 2021
BACKGROUND & AIMS Enteral nutrition (EN) and parenteral nutrition (PN) enriched with omega-3 ... more BACKGROUND & AIMS Enteral nutrition (EN) and parenteral nutrition (PN) enriched with omega-3 polyunsaturated fatty acids (PUFA) have beneficial effects in critical illness. This study aimed to assess the combined effect of EN and supplemental PN enriched with omega-3 PUFA on blood oxygenation in intensive care unit (ICU) patients. METHODS Single-center, prospective, randomized, controlled, double-blind, phase III trial conducted from 10/2013 to 11/2017. A total of 100 ICU patients (18-85 years, APACHE II score > 15) requiring mechanical ventilation were randomly assigned to received combined EN and PN either with omega-3 PUFA (omega-3 group) or without (control group) for up to 28 days. Primary endpoint: 'change of PaO2/FiO2 from day (D) 1 to D4'. Secondary endpoints: lung function parameters, ICU complications, length of hospital stay, days free of ICU care/ventilation/sedation/catecholamine treatment, mortality, erythrocyte fatty acid composition, inflammatory parameters. Safety parameters: standard laboratory assessment, vital signs, physical examination, SOFA score, adverse events. RESULTS Combined EN and PN covered energy requirements to more than 80%. Blood oxygenation (ΔPaO2/FiO2 from D1 to D4: -1.3 ± 83.7, n = 42, and 13.3 ± 86.1, n = 39, in omega-3 and control group, respectively, p = 0.7795) and other lung function parameters did not differ between groups but days free of catecholamine treatment were significantly higher in the omega-3 group (~4 days, p = 0.0481). On D6, significantly more patients in the omega-3 group tolerated EN alone (51.0% vs. 29.8%, p = 0.0342). Eicosapentaenoic acid (EPA) content in erythrocytes was significantly increased in the omega-3 group at last observation compared with the control group (ΔEPA: 0.928 ± 0.808% vs. -0.024 ± 0.190%, p < 0.0001). No further significant group differences were detected. CONCLUSIONS Enteral and supplemental PN both enriched with omega-3 PUFA did not improve lung function but allowed earlier weaning from catecholamine treatment and PN. Supplemental PN succeeded to adequately cover energy requirements in critically ill patients. TRIAL REGISTRATION www.clinicaltrials.gov, registration number: NCT01162928.
Frontiers in Immunology, Oct 2, 2018
Prostaglandins, Leukotrienes and Essential Fatty Acids, 2016
Pain is a complex sensation that may be protective or cause undue suffering and loss of function,... more Pain is a complex sensation that may be protective or cause undue suffering and loss of function, depending on the circumstances. Peripheral nociceptor neurons (PNs) innervate most tissues, and express ion channels, nocisensors, which depolarize the cell in response to intense stimuli and numerous substances. Inflamed tissues manifest inflammatory hyperalgesia in which the threshold for pain and the response to painful stimuli are decreased and increased, respectively. Constituents of the inflammatory milieu sensitize PNs, thereby contributing to hyperalgesia. Polyunsaturated fatty acids undergo enzymatic and free radical-mediated oxygenation into an array of bioactive metabolites, oxygenated polyunsaturated fatty acids (oxy-PUFAs), including the classic eicosanoids. Oxy-PUFA production is enhanced during inflammation. Pioneering studies by Vane and colleagues from the early 1970s first implicated classic eicosanoids in the pain associated with inflammation. Here, we review the production and action of oxy-PUFAs that are not classic eicosanoids, but nevertheless are produced in injured/ inflamed tissues and activate or sensitize PNs. In general, oxy-PUFAs that sensitize PNs may do so directly, by activation of nocisensors, ion channels or GPCRs expressed on the surface of PNs, or indirectly, by increasing the production of inflammatory mediators that activate or sensitize PNs. We focus on oxy-PUFAs that act directly on PNs. Specifically, we discuss the role of arachidonic acid-derived 12S-HpETE, HNE, ONE, PGA2, iso-PGA2 and 15d-PGJ2, 5,6-and 8,9-EET, PGE2-G and 8R,15S-diHETE, as well as the linoleic acid-derived 9-and 13-HODE in inducing acute nocifensive behavior and/or inflammatory hyperalgesia in rodents. The nocisensors TRPV1, TRPV4 and TRPA1, and putative Gαs-type GPCRs are the PN targets of these oxy-PUFAs.
The Journal of Immunology, May 1, 2013
Journal of Clinical Investigation, 2015
Frontiers Research Topics, 2013
The Journal of Immunology, 2001
European Journal of Immunology, 2010
European Journal of Immunology, 1997
The putative effects of interleukin (IL)-7, operating in the context of extracellular matrix (ECM... more The putative effects of interleukin (IL)-7, operating in the context of extracellular matrix (ECM), on the adhesion of human T cells were examined. Recombinant human, IL-7 was found to bind ECM or fibronectin (FN) with IC50 values of 10-100 nM. Nanogram amounts of both soluble and, especially, FN- or ECM-bound IL-7, which differentially affected the morphologies of FN-adherent T cells, induced the adhesion of resting CD4+ and CD8+ T cells in dose-dependent and beta 1 integrin-dependent manners. Under static and flow conditions, soluble IL-7 also induced the binding of unstimulated T cells to vascular cell adhesion molecule-1, suggesting that this cytokine can also modulate integrin binding to endothelial cell ligands. The effects of affinity modulation by IL-7 of FN-specific beta 1 integrins depend on the presence of soluble FN, which inhibited T cell adhesion to FN induced by FN-bound IL-7 or by an integrin-specific affinity-modulating monoclonal antibody, but not by soluble IL-7 or phorbol 12-myristate 13-acetate. These findings provide an example of a major ECM integrin ligand, FN, which is capable of modulating its adhesive interactions with specific immune cells by associating with and presenting a cytokine in a bio-active state.
European Journal of Clinical Investigation, 2018
Neutrophils are critically involved in host defence and they also modulate the inflammatory proce... more Neutrophils are critically involved in host defence and they also modulate the inflammatory process. Turning the inflammatory response towards a resolutive outcome requires a dialogue between apoptotic neutrophils and proresolving macrophages through complex key molecular interactions controlling efferocytosis, anti-inflammatory reprogramming and ultimately immune regulation. In this review, we will first focus on recent molecular analyses aiming at characterizing the role of proteins expressed on apoptotic neutrophils and their cognate partners expressed on macrophages in the resolution of inflammation. These will include chemokine receptors and their ligands and annexin A1 and its receptor FPR2. We will next depict how the structural and enzymatic properties of proteinase 3 (PR3), the autoantigen in vasculitis, allow its expression on apoptotic neutrophils, which in turn affects efferocytosis and immune response associated with the clearance of apoptotic cells. This example illustrates that the fate of apoptotic neutrophils directly influences the resolution of inflammation and immune responses thereby potentially contributing to systemic and nonresolving inflammation as well as autoimmunity.
The FASEB Journal, 2021
The resolution of inflammation facilitates proper wound healing and limits tissue repair short of... more The resolution of inflammation facilitates proper wound healing and limits tissue repair short of exaggerated fibrotic scarring. The atypical chemokine receptor (ACKR)2/D6 scavenges inflammatory chemokines, while IFN‐β is a recently unveiled pro‐resolving cytokine. Both effector molecules limit acute inflammatory episodes and promote their resolution in various organs. Here, we found fibrotic skin lesions from ACKR2−/− mice presented increased epidermal and dermal thickening, atrophy of the subcutaneous adipose tissue, augmented disorientation of collagen deposition, and enhanced deformation and loss of hair follicles compared to WT counterparts. In addition, affected skin sections from ACKR2−/− mice contained reduced levels of the pro‐resolving mediators IFN‐β and IL‐10, but increased levels of the pro‐inflammatory chemokines CCL2 and 3, the pro‐fibrotic cytokine TGF‐β, and the immune‐stimulating cytokine IL‐12. Notably, treatment with exogenous IFN‐β rescued, at least in part, all the pro‐fibrotic outcomes and lesion size in ACKR2−/− mice and promoted expression of the pro‐resolving enzyme 12/15‐lipoxygenase (LO) in both ACKR2−/− and WT mice. Moreover, Ifnb−/− mice displayed enhanced pro‐fibrotic indices upon exposure to bleomycin. These findings suggest ACKR2 is an important mediator in limiting inflammatory skin fibrosis and acts via IFN‐β production to promote the resolution of inflammation and minimize tissue scaring.
American Journal of Physiology-Cell Physiology, 2020
Neutrophils are polymorphonuclear leukocytes that play a central role in host defense against inf... more Neutrophils are polymorphonuclear leukocytes that play a central role in host defense against infection and tissue injury. They are rapidly recruited to the inflamed site and execute a variety of functions to clear invading pathogens and damaged cells. However, many of their defense mechanisms are capable of inflicting collateral tissue damage. Neutrophil-driven inflammation is a unifying mechanism underlying many common diseases. Efficient removal of neutrophils from inflammatory loci is critical for timely resolution of inflammation and return to homeostasis. Accumulating evidence challenges the classical view that neutrophils represent a homogeneous population and that halting neutrophil influx is sufficient to explain their rapid decline within inflamed loci during the resolution of protective inflammation. Hence, understanding the mechanisms that govern neutrophil functions and their removal from the inflammatory locus is critical for minimizing damage to the surrounding tissue...
Blood
Innate immune neutrophils provide the first line of host defense against bacterial infections. Ne... more Innate immune neutrophils provide the first line of host defense against bacterial infections. Neutrophils under steady state rely almost entirely on glycolysis and exhibit very low levels of oxidative phosphorylation. The metabolite lactate has long been considered a "waste byproduct" of cell metabolism which accumulates during inflammation and sepsis. Increased plasma lactate levels in human patients is used as a marker for sepsis diagnosis. However, the direct effector actions of lactate, particularly in regulating neutrophil mobilization and function during inflammation has remained obscure. To better understand the metabolic consequences of BM neutrophil activation during the onset of inflammation, we tested how bacterial lipopolysaccharides (mimicking gram negative bacterial inflammation) introduced intraperitoneally (i.p.) affect neutrophil metabolism and mobilization. RNAseq of sorted BM neutrophils revealed that LPS-activated neutrophils upregulate enzymes catalyz...
Apoptosis
ARTS (Sept4_i2) is a pro-apoptotic protein and a product of the Sept4 gene. ARTS acts upstream of... more ARTS (Sept4_i2) is a pro-apoptotic protein and a product of the Sept4 gene. ARTS acts upstream of mitochondria to initiate caspase activation. ARTS induces apoptosis by specifically binding XIAP and allowing de-repression of active caspases required for Mitochondrial Outer Membrane Permeabilzation (MOMP). Moreover, ARTS promotes apoptosis by inducing ubiquitin-mediated degradation of both major anti-apoptotic proteins XIAP and Bcl-2. In the resolution phase of inflammation, the infiltrating leukocytes, which execute the acute innate response, undergo apoptosis and are subsequently cleared by phagocytic macrophages (i.e . efferocytosis). In this course, macrophages undergo reprogramming from inflammatory, to anti-inflammatory, and eventually to resolving macrophages that leave the injury sites. Since engulfment of apoptotic leukocytes is a key signaling step in macrophage reprogramming and resolution of inflammation, we hypothesized that a failed apoptosis in leukocytes in vivo would result in an impaired resolution process. To test this hypothesis, we utilized the Sept4/ARTS −/− mice, which exhibit resistance to apoptosis in many cell types. During zymosan A-induced peritonitis, Sept4/ARTS −/− mice exhibited impaired resolution of inflammation, characterized by reduced neutrophil apoptosis, macrophage efferocytosis and expression of pro-resolving mediators. This was associated with increased pro-inflammatory cytokines and reduced anti-inflammatory cytokines, secreted by resolution-phase macrophages. Moreover, ARTS overexpression in leukocytes in vitro promoted an anti-inflammatory behavior. Overall, our results suggest that ARTS is a key master-regulator necessary for neutrophil apoptosis, macrophage efferocytosis and reprogramming to the pro-resolving phenotype during the resolution of inflammation.