Melanocortin 1 Receptor Deficiency in Hematopoietic Cells Promotes the Expansion of Inflammatory Leukocytes in Atherosclerotic Mice

Melanocortin receptor 1 (MC1-R) is expressed in leukocytes, where it mediates anti-inflammatory actions. We have previously observed that global deficiency of MC1-R signaling perturbs cholesterol homeostasis, increases arterial leukocyte accumulation and accelerates atherosclerosis in apolipoprotein...

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Autores principales:	James J. Kadiri, Sina Tadayon, Keshav Thapa, Anni Suominen, Maija Hollmén, Petteri Rinne
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	melanocortin 1 receptor atherosclerosis CD4+ T cell inflammation bone marrow transplantation hematopoiesis Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/e5f3cf79c17b496eb2af18087261fa12
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spelling	oai:doaj.org-article:e5f3cf79c17b496eb2af18087261fa122021-11-19T06:26:07ZMelanocortin 1 Receptor Deficiency in Hematopoietic Cells Promotes the Expansion of Inflammatory Leukocytes in Atherosclerotic Mice1664-322410.3389/fimmu.2021.774013https://doaj.org/article/e5f3cf79c17b496eb2af18087261fa122021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.774013/fullhttps://doaj.org/toc/1664-3224Melanocortin receptor 1 (MC1-R) is expressed in leukocytes, where it mediates anti-inflammatory actions. We have previously observed that global deficiency of MC1-R signaling perturbs cholesterol homeostasis, increases arterial leukocyte accumulation and accelerates atherosclerosis in apolipoprotein E knockout (Apoe-/-) mice. Since various cell types besides leukocytes express MC1-R, we aimed at investigating the specific contribution of leukocyte MC1-R to the development of atherosclerosis. For this purpose, male Apoe-/- mice were irradiated, received bone marrow from either female Apoe-/- mice or MC1-R deficient Apoe-/- mice (Apoe-/- Mc1re/e) and were analyzed for tissue leukocyte profiles and atherosclerotic plaque phenotype. Hematopoietic MC1-R deficiency significantly elevated total leukocyte counts in the blood, bone marrow and spleen, an effect that was amplified by feeding mice a cholesterol-rich diet. The increased leukocyte counts were largely attributable to expanded lymphocyte populations, particularly CD4+ T cells. Furthermore, the number of monocytes was elevated in Apoe-/- Mc1re/e chimeric mice and it paralleled an increase in hematopoietic stem cell count in the bone marrow. Despite robust leukocytosis, atherosclerotic plaque size and composition as well as arterial leukocyte counts were unaffected by MC1-R deficiency. To address this discrepancy, we performed an in vivo homing assay and found that MC1-R deficient CD4+ T cells and monocytes were preferentially entering the spleen rather than homing in peri-aortic lymph nodes. This was mechanistically associated with compromised chemokine receptor 5 (CCR5)-dependent migration of CD4+ T cells and a defect in the recycling capacity of CCR5. Finally, our data demonstrate for the first time that CD4+ T cells also express MC1-R. In conclusion, MC1-R regulates hematopoietic stem cell proliferation and tissue leukocyte counts but its deficiency in leukocytes impairs cell migration via a CCR5-dependent mechanism.James J. KadiriJames J. KadiriSina TadayonKeshav ThapaKeshav ThapaAnni SuominenAnni SuominenMaija HollménPetteri RinnePetteri RinneFrontiers Media S.A.articlemelanocortin 1 receptoratherosclerosisCD4+ T cellinflammationbone marrow transplantationhematopoiesisImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	melanocortin 1 receptor atherosclerosis CD4+ T cell inflammation bone marrow transplantation hematopoiesis Immunologic diseases. Allergy RC581-607
spellingShingle	melanocortin 1 receptor atherosclerosis CD4+ T cell inflammation bone marrow transplantation hematopoiesis Immunologic diseases. Allergy RC581-607 James J. Kadiri James J. Kadiri Sina Tadayon Keshav Thapa Keshav Thapa Anni Suominen Anni Suominen Maija Hollmén Petteri Rinne Petteri Rinne Melanocortin 1 Receptor Deficiency in Hematopoietic Cells Promotes the Expansion of Inflammatory Leukocytes in Atherosclerotic Mice
description	Melanocortin receptor 1 (MC1-R) is expressed in leukocytes, where it mediates anti-inflammatory actions. We have previously observed that global deficiency of MC1-R signaling perturbs cholesterol homeostasis, increases arterial leukocyte accumulation and accelerates atherosclerosis in apolipoprotein E knockout (Apoe-/-) mice. Since various cell types besides leukocytes express MC1-R, we aimed at investigating the specific contribution of leukocyte MC1-R to the development of atherosclerosis. For this purpose, male Apoe-/- mice were irradiated, received bone marrow from either female Apoe-/- mice or MC1-R deficient Apoe-/- mice (Apoe-/- Mc1re/e) and were analyzed for tissue leukocyte profiles and atherosclerotic plaque phenotype. Hematopoietic MC1-R deficiency significantly elevated total leukocyte counts in the blood, bone marrow and spleen, an effect that was amplified by feeding mice a cholesterol-rich diet. The increased leukocyte counts were largely attributable to expanded lymphocyte populations, particularly CD4+ T cells. Furthermore, the number of monocytes was elevated in Apoe-/- Mc1re/e chimeric mice and it paralleled an increase in hematopoietic stem cell count in the bone marrow. Despite robust leukocytosis, atherosclerotic plaque size and composition as well as arterial leukocyte counts were unaffected by MC1-R deficiency. To address this discrepancy, we performed an in vivo homing assay and found that MC1-R deficient CD4+ T cells and monocytes were preferentially entering the spleen rather than homing in peri-aortic lymph nodes. This was mechanistically associated with compromised chemokine receptor 5 (CCR5)-dependent migration of CD4+ T cells and a defect in the recycling capacity of CCR5. Finally, our data demonstrate for the first time that CD4+ T cells also express MC1-R. In conclusion, MC1-R regulates hematopoietic stem cell proliferation and tissue leukocyte counts but its deficiency in leukocytes impairs cell migration via a CCR5-dependent mechanism.
format	article
author	James J. Kadiri James J. Kadiri Sina Tadayon Keshav Thapa Keshav Thapa Anni Suominen Anni Suominen Maija Hollmén Petteri Rinne Petteri Rinne
author_facet	James J. Kadiri James J. Kadiri Sina Tadayon Keshav Thapa Keshav Thapa Anni Suominen Anni Suominen Maija Hollmén Petteri Rinne Petteri Rinne
author_sort	James J. Kadiri
title	Melanocortin 1 Receptor Deficiency in Hematopoietic Cells Promotes the Expansion of Inflammatory Leukocytes in Atherosclerotic Mice
title_short	Melanocortin 1 Receptor Deficiency in Hematopoietic Cells Promotes the Expansion of Inflammatory Leukocytes in Atherosclerotic Mice
title_full	Melanocortin 1 Receptor Deficiency in Hematopoietic Cells Promotes the Expansion of Inflammatory Leukocytes in Atherosclerotic Mice
title_fullStr	Melanocortin 1 Receptor Deficiency in Hematopoietic Cells Promotes the Expansion of Inflammatory Leukocytes in Atherosclerotic Mice
title_full_unstemmed	Melanocortin 1 Receptor Deficiency in Hematopoietic Cells Promotes the Expansion of Inflammatory Leukocytes in Atherosclerotic Mice
title_sort	melanocortin 1 receptor deficiency in hematopoietic cells promotes the expansion of inflammatory leukocytes in atherosclerotic mice
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/e5f3cf79c17b496eb2af18087261fa12
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Melanocortin 1 Receptor Deficiency in Hematopoietic Cells Promotes the Expansion of Inflammatory Leukocytes in Atherosclerotic Mice

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