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Myeloid adrenergic signaling via CaMKII forms a feedforward loop of catecholamine biosynthesis.

ABSTRACT: Type 2 immune response has been shown to facilitate cold-induced thermogenesis and browning of white fat. However, whether alternatively activated macrophages produce catecholamine and substantially promote adaptive thermogenesis in adipose tissue remains controversial. Here, we show that tyrosine hydroxylase (TyrH), a rate-limiting enzyme of catecholamine biosynthesis, was expressed and phosphorylated in adipose-resident macrophages. In addition, the plasma level of adrenaline was increased by cold stress in mice, and treatment of macrophages with adrenaline stimulated phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and TyrH. Genetic and pharmacological inhibition of CaMKII or PKA signaling diminished adrenaline-induced phosphorylation of TyrH in primary macrophages. Consistently, overexpression of constitutively active CaMKII upregulated basal TyrH phosphorylation, while suppressing the stimulatory effect of adrenaline on TyrH in macrophages. Myeloid-specific disruption of CaMKII? suppressed both the cold-induced production of norepinephrine and adipose UCP1 expression in vivo and the stimulatory effect of adrenaline on macrophage-dependent activation of brown adipocytes in vitro. Lack of CaMKII signaling attenuated catecholamine production mediated by cytokines IL-4 and IL-13, key inducers of type 2 immune response in primary macrophages. Taken together, these results suggest a feedforward mechanism of adrenaline in adipose-resident macrophages, and that myeloid CaMKII signaling plays an important role in catecholamine production and subsequent beige fat activation.

SUBMITTER: Luo Y

PROVIDER: S-EPMC5907839 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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Myeloid adrenergic signaling via CaMKII forms a feedforward loop of catecholamine biosynthesis.

Luo Yan Y Liu Bilian B Yang Xin X Ma Xiaoxiao X Zhang Xing X Bragin Denis E DE Yang Xuexian O XO Huang Wendong W Liu Meilian M

Journal of molecular cell biology 20171001 5

Type 2 immune response has been shown to facilitate cold-induced thermogenesis and browning of white fat. However, whether alternatively activated macrophages produce catecholamine and substantially promote adaptive thermogenesis in adipose tissue remains controversial. Here, we show that tyrosine hydroxylase (TyrH), a rate-limiting enzyme of catecholamine biosynthesis, was expressed and phosphorylated in adipose-resident macrophages. In addition, the plasma level of adrenaline was increased by ...[more]

PMID: 29087480

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Project description:BackgroundNeuroblastoma is the most common solid tumor in infants accounting for approximately 15% of all cancer-related deaths. Over 50% of high-risk neuroblastoma relapse, emphasizing the need of novel drug targets and therapeutic strategies. In neuroblastoma, chromosomal gains at chromosome 17q, including IGF2BP1, and MYCN amplification at chromosome 2p are associated with adverse outcome. Recent, pre-clinical evidence indicates the feasibility of direct and indirect targeting of IGF2BP1 and MYCN in cancer treatment.MethodsCandidate oncogenes on 17q were identified by profiling the transcriptomic/genomic landscape of 100 human neuroblastoma samples and public gene essentiality data. Molecular mechanisms and gene expression profiles underlying the oncogenic and therapeutic target potential of the 17q oncogene IGF2BP1 and its cross-talk with MYCN were characterized and validated in human neuroblastoma cells, xenografts and PDX as well as novel IGF2BP1/MYCN transgene mouse models.ResultsWe reveal a novel, druggable feedforward loop of IGF2BP1 (17q) and MYCN (2p) in high-risk neuroblastoma. This promotes 2p/17q chromosomal gains and unleashes an oncogene storm resulting in fostered expression of 17q oncogenes like BIRC5 (survivin). Conditional, sympatho-adrenal transgene expression of IGF2BP1 induces neuroblastoma at a 100% incidence. IGF2BP1-driven malignancies are reminiscent to human high-risk neuroblastoma, including 2p/17q-syntenic chromosomal gains and upregulation of Mycn, Birc5, as well as key neuroblastoma circuit factors like Phox2b. Co-expression of IGF2BP1/MYCN reduces disease latency and survival probability by fostering oncogene expression. Combined inhibition of IGF2BP1 by BTYNB, MYCN by BRD inhibitors or BIRC5 by YM-155 is beneficial in vitro and, for BTYNB, also.ConclusionWe reveal a novel, druggable neuroblastoma oncogene circuit settling on strong, transcriptional/post-transcriptional synergy of MYCN and IGF2BP1. MYCN/IGF2BP1 feedforward regulation promotes an oncogene storm harboring high therapeutic potential for combined, targeted inhibition of IGF2BP1, MYCN expression and MYCN/IGF2BP1-effectors like BIRC5.

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Myeloid adrenergic signaling via CaMKII forms a feedforward loop of catecholamine biosynthesis.

Publications

Myeloid adrenergic signaling via CaMKII forms a feedforward loop of catecholamine biosynthesis.

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