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Multiple variants of TNFRSF1Amutations may impact conventional and regulatory CD4+T cell functions in TRAPS patients. TNFR‐associated periodic syndrome is an autoinflammatory disorder caused by autosomal‐dominant mutations in TNFRSF1A, the gene encoding for TNFR superfamily 1A. The lack of knowledge in the field of TNFR‐associated periodic syndrome biology is clear, particularly in the context of control of immune self‐tolerance. We investigated how TNF‐α/TNFR superfamily 1A signaling can affect T cell biology, focusing on conventional CD4+CD25−and regulatory CD4+CD25+T cell functions in patients with TNFR‐associated periodic syndrome carrying either high or low penetrance TNFRSF1Amutations. Specifically, we observed that in high penetrance TNFR‐associated periodic syndrome, at the molecular level, these alterations were secondary to a hyperactivation of the ERK1/2, STAT1/3/5, mammalian target of rapamycin, and NF‐κB pathways in conventional T cells. In addition, these patients had a lower frequency of peripheral regulatory T cells, which also displayed a defective suppressive phenotype. These alterations were partially found in low penetrance TNFR‐associated periodic syndrome, suggesting a specific link between the penetrance of the TNFRSF1Amutation and the observed T cell phenotype. Taken together, our data envision a novel role for adaptive immunity in the pathogenesis of TNFR‐associated periodic syndrome involving both CD4+conventional T cells and Tregs, suggesting a novel mechanism of inflammation in the context of autoinflammatory disorders.

Activation of CBs on HLMs reduces production of lymph/angiogenic factors; a possible novel strategy to modulate macrophage‐assisted vascular remodeling. 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‐α 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.