Nature. A new immune mechanism that regulates fat sympathetic nerves and heat production.

Tangxiaotang sympathetic nervous system controls various physiological processes, such as vascular tension, cardiac output, glandular secretion and thermogenesis.when the environment changes, the sympathetic nerve maintains steady state by controlling these physiological processes, mainly by releasing various neurotransmitters from local axons to regulate the activities of terminal organs and cell tissues [2].due to the complexity of target cell innervation and the emerging population of sympathetic neurons, the molecular mechanism of bidirectional communication between sympathetic nerve and target cell remains to be elucidated.the sympathetic nervous system drives heat production of brown and beige fat by releasing norepinephrine [3].in this process, transcription factor PRDM16, endoplasmic reticulum protein clstn3 β and neurotrophic factor S100B are involved in this process, which means that heat source adipose tissue is a suitable model for studying the communication between peripheral target cells and sympathetic nervous system.previous studies have shown that innate immune cells, such as anti-inflammatory macrophages, eosinophils and type II innate lymphocytes (ilc2s), can regulate fat thermogenesis [4].however, the role of acquired immune cells in this process has not been fully elucidated.on February 20, 2020, the team of Bruce M. Spiegelman from Harvard Medical School Dana Faber Cancer Research Institute (together as Hu Bo, Jin Cheng Cheng Cheng, Zeng Xing) published an online article in the journal Nature, γ δ T cells and adipocyte il-17rc control fat innovation and thermogenesis, which reported T cells, especially γ δ T cells regulate sympathetic innervation via IL-17 receptor C (il-17rc).the loss of il-17rc specificity in adipose tissue can reduce the secretion of TGF β 1 in adipocytes, and then damage the local sympathetic innervation, resulting in obesity and other metabolic manifestations related to thermogenesis. This phenomenon can be saved by restoring the expression of TGF β 1.in addition, the deficiency of δ T cells and il-17rc can also damage the sympathetic innervation of other tissues such as salivary glands.this study shows that T cells and parenchymal cells of various organs work together to regulate sympathetic innervation.researchers used a variety of mouse models RAG2 - / -, TCRA - / -, mumt - / -, and TCRD - / - (corresponding to t, B cell deletion, α β T cell deletion, B cell deletion, and γ δ T cell deletion, respectively) to evaluate the role of different types of lymphocytes in adaptive thermogenesis.compared with wild-type mice, RAG2 - / - and TCRD - / - mice showed poor cold tolerance, while TCRA - / - and mumt - / - mice showed normal or slightly impaired cold tolerance, and TCRD - / - mice showed decreased oxygen consumption and increased fat content in brown adipose tissue under cold experimental conditions.it is suggested that adaptive thermogenesis can be activated by γ δ T cells, and its deletion may lead to brown adipose tissue dysfunction.further researchers found that cold exposure significantly increased IL-17F in brown adipose tissue, and IL-17F - / - mice also demonstrated that IL-17F was involved in adaptive thermogenesis.in mice, il-17rc, the receptor of IL-17F, is highly expressed in heat source adipocytes, so the researchers used adipocyte specific il-17rc knockout (adil17rc - / -) mice, heat source adipocyte specific il-17rc knockout (UCP1 cre adil17rcfl / FL) mice and il-17rc knockout + vg6 γ δ The results showed that the il-17rc pathway in the thermogenic adipocytes was necessary for the adaptive thermogenesis of δ T cells.what is the mechanism of impaired adaptive heat production? The researchers found that the cold tolerance and oxygen consumption of adil17rc - / - mice decreased at low temperature, but there was no difference in oxygen consumption between adil17rc - / - mice and wild-type mice after injection of β 3-adrenergic agonist, suggesting that the damage of heat generation in adil17rc - / - mice may be caused by signal defect upstream of β 3-adrenoceptor. in brown adipose tissue, sympathetic nerve is the main source of epinephrine. Through the tyrosine hydroxylase (th) immunostaining of different mouse models, the researchers found that γ δ T cells and adipocytes il-17rc signaling pathway jointly promote the sympathetic innervation of adaptive heat source tissues. furthermore, with the help of slc17a8 (VGLUT3) - IRES CRE mouse system, which was established before, through the injection of aav-hm3dq mcerry to mediate CRE expression in VGLUT3 neurons, the researchers detected the thermal response of brown adipose tissue in adil17rc - / - mice and vg6 γ δ T cell overexpression transgenic mice, and found that the thermal response of il-17rc knockout mice decreased, while that of γ δ T cells decreased The cold resistance of il-17rc knockout mice can be saved by enhancing the fat specific neurotrophic pathway clstn3 β – S100B. a series of experimental results show that il-17rc can activate the sympathetic innervation of heat source fat, and its absence will lead to the damage of this innervation, which is still the same in other tissues such as salivary glands. so how does the γ δ t-il-17rc pathway regulate sympathetic innervation? The researchers analyzed the proteome and transcriptome of brown adipose tissue in wild-type mice and il-17rc knockout mice. Compared with wild-type mice, the signal pathways of down-regulated genes in knockout mice were enriched in epithelial mesenchymal transition and TGF β signaling pathways. At the same time, the expression levels of TGF β 1 and its target genes were also decreased in knockout mice. IL-17F is known to activate the expression of TGF β 1 in endothelial cells, and this phenomenon has also been observed in adipocytes. the above results indicate that IL-17F can activate the expression of TGF β 1, and the damage of γ δ t-il17rc pathway leads to the down regulation of TGF β 1 expression, and this function is manifested in many tissues such as adipose tissue, salivary gland and lung tissue. next, in order to verify that TGF β 1 does play a role, the researchers overexpressed TGF β 1 in il-17rc knockout mice and blocked or inhibited TGF β 1 expression in wild-type mice. The results showed that the cold tolerance of mice increased and decreased respectively. in addition, the expression of TGF β 1 induced by AAV also increased the immunostaining of th in salivary glands. these results indicate that the γ δ t-il17rc pathway plays an important role in the activation of sympathetic innervation, which is dependent on TGF β 1 signaling pathway. in general, researchers have found an immune mechanism that regulates sympathetic nerve in multiple tissues. In particular, in heat source adipose tissue, γ δ T cells and il-17rc jointly regulate sympathetic innervation and thermogenesis through TGF β 1 pathway. this study provides potential therapeutic strategies for obesity and a variety of metabolic disorders related diseases. this paper is a joint work of golden orange, which has established its own laboratory (Perelman School of medicine, University of Pennsylvania).