Anouk Wezel1, H Maxime Lagraauw2, Daniël van der Velden3, Saskia C A de Jager4, Paul H A Quax5, Johan Kuiper2, Ilze Bot6. 1. Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. 2. Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. 3. Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. 4. Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands. 5. Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. 6. Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: i.bot@lacdr.leidenuniv.nl.
Abstract
AIMS: Activated mast cells have been identified in the intima and perivascular tissue of human atherosclerotic plaques. As mast cells have been described to release a number of chemokines that mediate leukocyte fluxes, we propose that activated mast cells may play a pivotal role in leukocyte recruitment during atherosclerotic plaque progression. METHODS AND RESULTS: Systemic IgE-mediated mast cell activation in apoE(-/-)μMT mice resulted in an increase in atherosclerotic lesion size as compared to control mice, and interestingly, the number of neutrophils was highly increased in these lesions. In addition, peritoneal mast cell activation led to a massive neutrophil influx into the peritoneal cavity in C57Bl6 mice, whereas neutrophil numbers in mast cell deficient Kit(W(-sh)/W(-sh)) mice were not affected. Within the newly recruited neutrophil population, increased levels of CXCR2(+) and CXCR4(+) neutrophils were observed after mast cell activation. Indeed, mast cells were seen to contain and release CXCL1 and CXCL12, the ligands for CXCR2 and CXCR4. Intriguingly, peritoneal mast cell activation in combination with anti-CXCR2 receptor antagonist resulted in decreased neutrophil recruitment, thus establishing a prominent role for the CXCL1/CXCR2 axis in mast cell-mediated neutrophil recruitment. CONCLUSIONS: Our data suggest that chemokines, and in particular CXCL1, released from activated mast cells induce neutrophil recruitment to the site of inflammation, thereby aggravating the ongoing inflammatory response and thus affecting plaque progression and destabilization.
AIMS: Activated mast cells have been identified in the intima and perivascular tissue of humanatherosclerotic plaques. As mast cells have been described to release a number of chemokines that mediate leukocyte fluxes, we propose that activated mast cells may play a pivotal role in leukocyte recruitment during atherosclerotic plaque progression. METHODS AND RESULTS: Systemic IgE-mediated mast cell activation in apoE(-/-)μMT mice resulted in an increase in atherosclerotic lesion size as compared to control mice, and interestingly, the number of neutrophils was highly increased in these lesions. In addition, peritoneal mast cell activation led to a massive neutrophil influx into the peritoneal cavity in C57Bl6 mice, whereas neutrophil numbers in mast cell deficient Kit(W(-sh)/W(-sh)) mice were not affected. Within the newly recruited neutrophil population, increased levels of CXCR2(+) and CXCR4(+) neutrophils were observed after mast cell activation. Indeed, mast cells were seen to contain and release CXCL1 and CXCL12, the ligands for CXCR2 and CXCR4. Intriguingly, peritoneal mast cell activation in combination with anti-CXCR2 receptor antagonist resulted in decreased neutrophil recruitment, thus establishing a prominent role for the CXCL1/CXCR2 axis in mast cell-mediated neutrophil recruitment. CONCLUSIONS: Our data suggest that chemokines, and in particular CXCL1, released from activated mast cells induce neutrophil recruitment to the site of inflammation, thereby aggravating the ongoing inflammatory response and thus affecting plaque progression and destabilization.
Authors: Emiliano Trias; Peter H King; Ying Si; Yuri Kwon; Valentina Varela; Sofía Ibarburu; Mariángeles Kovacs; Ivan C Moura; Joseph S Beckman; Olivier Hermine; Luis Barbeito Journal: JCI Insight Date: 2018-10-04
Authors: Simon Kennedy; Pasquale Maffia; Junxi Wu; Gianluca Grassia; Helen Cambrook; Armando Ialenti; Neil MacRitchie; Jaclyn Carberry; Roger M Wadsworth; Catherine Lawrence Journal: PeerJ Date: 2015-08-18 Impact factor: 2.984