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- Herrera-Hidalgo, Carmen, et al.
(författare)
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Macrophages contribute to vessel normalization during healing of ischemic injury
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Physiological regression of superfluous micro-vessels, vascular pruning, is observed during formation of functional vascular networks in fetal development. The current study investigates the vascular dynamics during healing of injured adult tissues in the mouse model of hind limb ischemia. We found that prompt angiogenesis that occurs in M. gastrocnemius to compensate for loss of tissue perfusion, results in blood vessel densities that are higher than those found in healthy muscles. Vessel density peaked at day 14 post ischemia to thereafter recede to normal levels by day 21, indicating that vessel pruning occurs during healing to ensure establishment of an optimal vascular tree. Macrophages are professional phagocytes and we found them present in high numbers at sites of ischemic injury, where they were positioned in close contact with the vascular network and displayed phagocytic activity at the time of vessel pruning. Interestingly, macrophage depletion between day 14 and 21 post-ischemia resulted in reduced vessel regression. Indeed, by using a reporter mouse for endothelial cells, we found that macrophages engulf endothelial cells at the ischemic site at this time point. Taken together, our results indicate a role for macrophages in vessel normalization by pruning superfluous vasculatur segments that form initially during healing of ischemic injuries.
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- Muntjewerff, Elke M., et al.
(författare)
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The anti-inflammatory peptide Catestatin blocks chemotaxis
- 2022
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Ingår i: Journal of Leukocyte Biology. - : John Wiley & Sons. - 0741-5400 .- 1938-3673. ; 112:2, s. 273-278
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Tidskriftsartikel (refereegranskat)abstract
- Increased levels of the anti-inflammatory peptide Catestatin (CST), a cleavage product of the pro-hormone chromogranin A, correlate with less severe outcomes in hypertension, colitis, and diabetes. However, it is unknown how CST reduces the infiltration of monocytes and macrophages (M phi s) in inflamed tissues. Here, it is reported that CST blocks leukocyte migration toward inflammatory chemokines. By in vitro and in vivo migration assays, it is shown that although CST itself is chemotactic, it blocks migration of monocytes and neutrophils to inflammatory attracting factor CC-chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 2 (CXCL2). Moreover, it directs CX(3)CR1(+) M phi s away from pancreatic islets. These findings suggest that the anti-inflammatory actions of CST are partly caused by its regulation of chemotaxis.
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- Ng, Henry, et al.
(författare)
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Circulating Markers of Neutrophil Extracellular Traps Are of Prognostic Value in Patients With COVID-19
- 2021
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1079-5642 .- 1524-4636. ; 41:2, s. 988-994
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Tidskriftsartikel (refereegranskat)abstract
- Objective:The full spectrum of coronavirus disease 2019 (COVID-19) infection ranges from asymptomatic to acute respiratory distress syndrome, characterized by hyperinflammation and thrombotic microangiopathy. The pathogenic mechanisms are poorly understood, but emerging evidence suggest that excessive neutrophil extracellular trap (NET) formation plays a key role in COVID-19 disease progression. Here, we evaluate if circulating markers of NETs are associated with COVID-19 disease severity and clinical outcome, as well as to markers of inflammation and in vivo coagulation and fibrinolysis.Approach and Results:One hundred six patients with COVID-19 with moderate to severe disease were enrolled shortly after hospital admission and followed for 4 months. Acute and convalescent plasma samples as well as plasma samples from 30 healthy individuals were assessed for markers of NET formation: citrullinated histone H3, cell-free DNA, NE (neutrophil elastase). We found that all plasma levels of NET markers were elevated in patients with COVID-19 relative to healthy controls, that they were associated with respiratory support requirement and short-term mortality, and declined to those found in healthy individuals 4 months post-infection. The levels of the NET markers also correlated with white blood cells, neutrophils, inflammatory cytokines, and C-reactive protein, as well as to markers of in vivo coagulation, fibrinolysis, and endothelial damage.Conclusions:Our findings suggest a role of NETs in COVID-19 disease progression, implicating their contribution to an immunothrombotic state. Further, we observed an association between circulating markers of NET formation and clinical outcome, demonstrating a potential role of NET markers in clinical decision-making, as well as for NETs as targets for novel therapeutic interventions in COVID-19.
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- Parv, Kristel
(författare)
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Macrophages and neutrophils in tissue homeostasis and recovery from ischemic injury
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neutrophils and macrophages have functions beyond protection against pathogens. The overall aim of the work presented in this thesis was to identify novel tasks for these innate immune cells in maintaining homeostasis. In the studies presented here, we explored macrophage roles in tissue recovery from ischemic injury and post-natal tissue development, and the origin and recruitment mechanisms of pro-angiogenic neutrophils (PANs) to the site of ischemic injury.In Study I, it was shown that perivascular macrophages at sites of ischemic injury adopt characteristics of mural cell identity. Combining genetic heritable fate mapping of macrophages with single-cell RNA-sequencing, we were able to demonstrate that macrophages downregulated the expression of myeloid markers, and upregulated those of mural cells. Depletion of macrophages during tissue healing demonstrated that macrophages also adopt important mural cell functions that are crucial for blood vessel maturation after ischemic injury. In Study II, it was shown that perivascular macrophages form cuff-like structures around vessels in the ischemic muscle following ischemia. Using genetically modified mouse models, we showed that these macrophages regulate bloodflow in an inducible NO Synthase (iNOS)-dependent manner, and this could be therapeutically targeted to improve tissue healing through local delivery of plasmid-encoded C-X-C Motif Chemokine Ligand 12 (CXCL12). In Study III, it was shown that recruitment of PANs to the site of ischemic injury is dependent on CD49d signalling, and the spleen contains a peripheral reservoir of PANs which is crucial for achieving adequate accumulation of PANs at the site of ischemic injury. We also showed that the release of splenic PANs in response to ischemic injury relies on sympathetic signalling and downregulation of CXCL12α in the splenic red pulp.In Study IV, it was shown that pancreatic tissue-resident macrophages are important for post-natal islet development, as depletion of macrophages using clodronate liposomes led to impaired glucose tolerance in adult mice. Further, neonatal infection with S. aureus led to reduced number of pancreatic macrophages and interfered with normal post-natal β cell development, leading to impaired glucose tolerance. In summary, the work presented here expands our understanding on the various roles of macrophages during ischemic injury and tissue development, and significantly advances our understanding of the origins and recruitment mechanisms of pro-angiogenic neutrophils during ischemic injury.
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- Parv, Kristel, et al.
(författare)
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Phagocytosis and Efferocytosis by Resident Macrophages in the Mouse Pancreas
- 2021
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media S.A.. - 1664-2392. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- The tissue microenvironment in the mouse pancreas has been shown to promote very different polarizations of resident macrophages with islet-resident macrophages displaying an inflammatory “M1” profile and macrophages in the exocrine tissue mostly displaying an alternatively activated “M2” profile. The impact of this polarization on tissue homeostasis and diabetes development is unclear. In this study, the ability of pancreas-resident macrophages to phagocyte bacterial and endogenous debris was investigated. Mouse endocrine and exocrine tissues were separated, and tissue-resident macrophages were isolated by magnetic immunolabeling. Isolated macrophages were subjected to flow cytometry for polarization markers and qPCR for phagocytosis-related genes. Functional in vitro investigations included phagocytosis and efferocytosis assays using pH-sensitive fluorescent bacterial particles and dead fluorescent neutrophils, respectively. Intravital confocal imaging of in situ phagocytosis and efferocytosis in the pancreas was used to confirm findings in vivo. Gene expression analysis revealed no significant overall difference in expression of most phagocytosis-related genes in islet-resident vs. exocrine-resident macrophages included in the analysis. In this study, pancreas-resident macrophages were shown to differ in their ability to phagocyte bacterial and endogenous debris depending on their microenvironment. This difference in abilities may be one of the factors polarizing islet-resident macrophages to an inflammatory state since phagocytosis has been found to imprint macrophage heterogeneity. It remains unclear if this difference has any implications in the development of islet dysfunction or autoimmunity.
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- Vågesjö, Evelina, et al.
(författare)
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Perivascular macrophages regulate blood flow following tissue damage
- 2021
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Ingår i: Circulation Research. - : Lippincott Williams & Wilkins. - 0009-7330 .- 1524-4571. ; 128:11, s. 1694-1707
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Ischemic injuries remain a leading cause of mortality and morbidity worldwide, and restoration of functional blood perfusion is vital to limit tissue damage and support healing.Objective: To reveal a novel role of macrophages in reestablishment of functional tissue perfusion following ischemic injury that can be targeted to improve tissue restoration.Methods and Results: Using intravital microscopy of ischemic hindlimb muscle in mice, and confocal microscopy of human tissues from amputated legs, we found that macrophages accumulated perivascularly in ischemic muscles, where they expressed high levels of iNOS (inducible nitric oxide [NO] synthase). Genetic depletion of iNOS specifically in macrophages (Cx3cr1-CreERT2;Nos2(fl/fl) or LysM-Cre;Nos2(fl/fl)) did not affect vascular architecture but highly compromised blood flow regulation in ischemic but not healthy muscle, which resulted in aggravated ischemic damage. Thus, the ability to upregulate blood flow was shifted from eNOS (endothelial)-dependence in healthy muscles to completely rely on macrophage-derived iNOS during ischemia. Macrophages in ischemic muscles expressed high levels of CXCR4 (C-X-C chemokine receptor type 4) and CCR2 (C-C chemokine receptor type 2), and local overexpression by DNA plasmids encoding the corresponding chemokines CXCL12 (stromal-derived factor 1) or CCL2 (chemokine [C-C motif] ligand 2) increased macrophage numbers, while CXCL12 but not CCL2 induced their perivascular positioning. As a result, CXCL12-overexpression increased the number of perfused blood vessels in the ischemic muscles, improved functional muscle perfusion in a macrophage-iNOS-dependent manner, and ultimately restored limb function.Conclusions: This study establishes a new function for macrophages during tissue repair, as they regulate blood flow through the release of iNOS-produced NO. Further, we demonstrate that macrophages can be therapeutically targeted to improve blood flow regulation and functional recovery of ischemic tissues.
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