Human lung-resident macrophages express CB1 and CB2 receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors

Abstract

Macrophages are pivotal effector cells in immune responses and tissue remodeling by producing a wide spectrum of mediators, including angiogenic and lymphangiogenic factors. Activation of cannabinoid receptor types 1 and 2 has been suggested as a new strategy to modulate angiogenesis in vitro and in vivo. We investigated whether human lung-resident macrophages express a complete endocannabinoid system by assessing their production of endocannabinoids and expression of cannabinoid receptors. Unstimulated human lung macrophage produce 2-arachidonoylglycerol, N-arachidonoyl-ethanolamine, N-palmitoyl-ethanolamine, and N-oleoyl-ethanolamine. On LPS stimulation, human lung macrophages selectively synthesize 2-arachidonoylglycerol in a calcium-dependent manner. Human lung macrophages express cannabinoid receptor types 1 and 2, and their activation induces ERK1/2 phosphorylation and reactive oxygen species generation. Cannabinoid receptor activation by the specific synthetic agonists ACEA and JWH-133 (but not the endogenous agonist 2-arachidonoylglycerol) markedly inhibits LPS-induced production of vascular endothelial growth factor-A, vascular endothelial growth factor-C, and angiopoietins and modestly affects IL-6 secretion.No significant modulation of TNF-a or IL-8/CXCL8 release was observed. The production of vascular endothelial growth factor-A by human monocyte-derived macrophages is not modulated by activation of cannabinoid receptor types 1 and 2. Given the prominent role of macrophage-assisted vascular remodeling in many tumors, we identified the expression of cannabinoid receptors in lung cancer-associated macrophages. Our results demonstrate that cannabinoid receptor activation selectively inhibits the release of angiogenic and lymphangiogenic factors from human lung macrophage but not from monocyte-derived macrophages. Activation of cannabinoid receptors on tissue-resident macrophages might be a novel strategy to modulate macrophage-assisted vascular remodeling in cancer and chronic inflammation. J. Leukoc. Biol. 99: 531-540; 2016.

Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis

“…Therefore, multicellular interactions in the lung constitute the fibrogenic environment and affect progression of the disease. In the lung, CB 1 R is expressed in different cell populations, including ATII cells (35), bronchial epithelial cells (36), and both resident and infiltrating alveolar macrophages (37). We found a high degree of colocalization of CB 1 R with the ATII cell marker SP-C ( Figure 4B).…”

“…On the other hand, human lung macrophages isolated from lungs adenocarcinoma patients, which display M2-like polarization, do not contain elevated levels of AEA following in vitro exposure to LPS (37). In addition, pulmonary inflammation induced by aerosolized LPS, which is not associated with significant cell damage, exhibited neutrophil infiltration and secretion of inflammatory cytokines but no increase in AEA in BALF (57).…”

Endocannabinoid hydrolysis inhibition unmasks that unsaturated fatty acids induce a robust biosynthesis of 2‐arachidonoyl‐glycerol and its congeners in human myeloid leukocytes

“…However, we show that most leukocytes do not biosynthesize substantial levels of 2‐AG in response to agonists recognized to activate the PLC pathway, either in the absence or in the presence of MAFP. One study showed that human lung macrophages stimulated with LPS synthesize more 2‐AG in the presence of a MAG lipase inhibitor but this increase of approximately 40% is modest compared to the impact MAFP had in our biosynthetic route involving UFAs …”

“…The synthesis of 2‐AG by human leukocytes is not well documented. Furthermore, efforts to induce 2‐AG biosynthesis in leukocytes led to 2‐AG levels lower than those required to activate the CB 2 receptor, for which 2‐AG has a Ki of ~145 nM . The classic 2‐AG biosynthetic pathway involves two enzymatic steps.…”

Physiological Roles of Mast Cells: Collegium Internationale Allergologicum Update 2019

“…VEGF-C and VEGF-D are crucial for the survival, proliferation, and migration of LECs by engaging VEGFR3 [155]. VEGF-A also influences lymphangiogenesis by recruiting immune cells (e.g., macrophages and mast cells) that produce VEGF-C and VEGF-D [9, 156]. Angiopoietins (ANGPT1 and ANGPT2) also modulate angiogenesis and lymphangiogenesis through the engagement of TIE1 and TIE2 receptors [157].…”