Anti-inflammatory state in fat tissue-sympathetic nerves
New report, published in Endocrinology, indicates that the sympathetic nerves keep up an anti-inflammatory state in the fat tissue.
More specifically, the activity of the sympathetic nervous system (SNS) and its β2-adrenoceptor signaling pathway sustain low levels of the production of the pro-inflammatory cytokine tumor necrosis factor (TNF)-α in macrophages of lean mice.
Adipose tissue macrophages (ATMs) are a specialized type of leukocyte present in lean and obese states that contribute to adipose tissue inflammation and remodeling in mammals. ATMs in mice are classified into 2 general subtypes based on functional characteristics.
Resident ATMs that manifest properties that overlap with those of alternatively activated (M2) macrophages and are associated with suppression of the immune response, and CD11c-positive cells that are associated with tissue damage, proinflammatory signaling, and the generation of T helper 1 cytokines such as TNF-α, a hallmark of classically activated (M1) macrophages.
Pro-inflammatory macrophages play a key role in the pathogenesis of the systemic low-grade chronic inflammation, associated with obesity and insulin resistance (Angela Castoldi et al., Front Immunol, 2016, 6:637).
ATMs in adipose tissue of lean animals are anti-inflammatory (2, 3), and the pathological factors that induce a functional transition in ATM polarization from M2 to M1 are therefore of interest. Saturated fatty acids activate inflammatory programs in resident ATMs. Toll-like pattern recognition receptors, in particular Toll-like receptor (TLR)4, mediate the proinflammatory effects of saturated fatty acids as well as those of lipopolysaccharide (LPS).
The abundance of inflammatory cytokines such as TNF-α is increased in brown adipose tissue (BAT) as well as in white adipose tissue (WAT) of obese animals (6). TNF-α suppresses the expression of uncoupling protein-1 (UCP-1) in brown adipocytes.
How resident macrophages’ function is regulated, in lean animals, remains poorly understood. It is known, however that the adipose tissue is heavily innervated by sympathetic/noradrenergic nerves.
The sympathetic nervous system (SNS) regulates lipid metabolism in adipose tissue. The central melanocortin system, in which α-melanocyte-stimulating hormone and agouti-related neuropeptide (AgRP) reciprocally control the activity of the melanocortin receptor (MCR), regulates lipid metabolism in WAT. Stimulation of central MCRs with the synthetic agonist melanotan II (MT-II) thus increases lipolysis in WAT via the SNS, whereas inhibition of MCRs increases expression of lipogenic genes in WAT.
Electrical stimulation of the medial hypothalamus stimulates thermogenesis as well as regulates glucose and lipid metabolism in BAT via sympathetic nerves innervating the tissue. The β3-adrenergic receptor (AR) is implicated in norepinephrine (NE)-induced lipolysis in WAT and thermogenesis in BAT. Catecholamines produced by ATMs have also been implicated in adaptive thermogenesis in WAT.
The study in Endocrinology by Lijun Tang and colleagues from the National Institute for Physiological Sciences, Okazaki, Aichi, Japan indicates that sympathetic nerves, innervating adipose tissue, down-regulate local TNF-α secretion directly via an effect on β2-adrenoceptors expressed by macrophages. The study also demonstrates that the brain melanocortin pathway is involved in the regulation of the anti-inflammatory state in lean mice via SNS-related mechanisms.
The authors suggest that, in the fat tissue of lean animals, a longstanding suppression of the β-adrenoceptor function may keep the balance of anti-inflammatory versus inflammatory state towards anti-inflammation, and this effect is not related to impairment of thermogenic function.
In conclusion, Lijun Tang and colleagues found that the SNS and β2-AR-PKA pathway suppress TNF-α production in adipose tissue of lean mice. The sympathetic nerve-immune system interface and the anti-inflammatory SNS impact on macrophages might be dysfunctional in obese animals, and perhaps, in humans with obesity.
Source: Endocrinology, 2015, 156:3680-94.
Read More: Endocrinology
Updates
2015
In an elegant 2015 commentary by Laurent Gautron, the author stated that the adipose tissue is progressively being revisited as an important site of convergence for multiple regulatory systems, including, most notably, the nervous and immune systems.
Commenting on the Endocrinology Tang et al. article, Dr. Gautron believes that this study provided additional evidence of the complex interactions that exist between adipocytes, sympathetic nerves and macrophages. As per Dr. Gautron, in their study, Tang et al. established that norepinephrine (noradrenaline), derived from the sympathetic nervous system, constitutively down-regulated the expression of TNF-α in mouse white and brown adipose tissues.
Figure 1. Schematic overview of the observations made by Tang et al. Previous studies clearly established that norepinephrine (NE) released in adipose tissue by nerve endings belonging to the sympathetic nervous system (sns) stimulates lipolysis. In addition, it is known that the release of free fatty acids (FFAs) by adipocytes is stimulated by TNF-α from resident macrophages. The findings from Tang et al. further indicated that NE suppressed TNF-α mRNA expressed by adipose macrophage via β2-adrenergic signaling. Interestingly, the authors also found that the central administration of AgRP, supposedly via the inhibition of the sympathetic outflow to adipose tissue, resulted in increased TNF-α mRNA. According to the lipostatic model of the regulation of energy balance, the cellular activity of AgRP neurons is under the influence of the circulating levels of leptin secreted by adipocytes. Together, these data demonstrate the complex interactions that exist between white adipocytes, hypothalamic neurons, sympathetic nerves, and macrophages. From: Toward a Neuroimmunoendocrinology of Adipose Tissue, by Laurent Gautron, Endocrinology. 2015 Oct;156(10):3485–3487. doi: 10.1210/en.2015-1735
Specifically, the β2-adrenergic receptor and protein kinase A signaling pathways were shown to be required for the down-regulation of TNF-α in adipose macrophages. In contrast, the β3-adrenergic receptor mediated norepinephrine-induced lipolysis.
According to Dr. Gautron relatively few studies have examined the immunomodulatory role of the sympathetic nervous system on adipose tissue. Interestingly, the author directed the reader’s attention towards the finding of the Tang et al. study, which showed that the lypolitic and immunosuppressive actions of norepinephrine were blunted in diet-induced obesity. This was correlated with a robust down-regulation of all 3 β-adrenergic receptors in white adipose tissue, thus indicating reduced adipose sympathetic functionality in obesity.
According to the author of this commentary, similar observations were made in obese humans. Of note, Dr. Gautron speculated: “Albeit we must be cautious in our interpretations until more definitive data are gathered regarding adipose sympathetic signaling in the obese, it is tempting to believe that reduced sympathetic outflow to adipose tissue may contribute to the enhanced inflammatory phenotype commonly seen in obesity”.
2021
A 2021 review by Xinmin Qian et al. highlighted the complex intercellular communications in the white adipose tissues (WAT), and particularly among adipocytes and other cell types such as residential and infiltrating immune cells, which are collectively under neuronal control.
As per the authors of this review, among the immune cells present in the WAT, macrophages/monocytes are the most intensively scrutinized immune types which display a high degree of heterogeneity. Importantly, previous studies have broadly described macrophage phenotype as anti-inflammatory and proinflammatory in lean and obese mice, respectively.
Furthermore, extensive characterization has divided the macrophages/monocytes further into distinct subtypes with differential expression profiles. The distinct subsets of macrophages have been characterized in close proximity to the sympathetic nerves which influence sympathetic input.
Figure 2. The emerging macrophage subsets in the white adipose tissues, including the ones associated with sympathetic nerves or vasculatures. The CX3CR1+ population expressing SLC6A2 and MAOA is identified as sympathetic neuron-associated macrophages (SAMs). Cold-induced neuroimmune cells (CINCs), a subset of Ly6C+ CCR2+ Cx3CR1+ monocytes/macrophages interacting with peripheral nerves, home to iWAT upon cold exposure and expressing BDNF. Two subpopulations identified in lung are also present in the WAT: The Lyve1loMHCIIhiCX3CR1hi subset resides in close distance with nerves, whereas the Lyve1hiMHCIIloCX3CR1lo subset is located preferentially alongside blood vessels. The groups of vasculature-associated adipose tissue macrophages (VAMs) are tightly associated with blood vessels, and they express high levels of CD206, CD301a, CD163, CD209, and Retnla/Fizz1. Lipid-associated macrophage (LAM) is identified in obesity expressing Trem2. BDNF, brain-derived neurotrophic factor; iWAT, inguinal white adipose tissues; MAOA, monoamine oxidase A; NE, norepinephrine; Retnla/Fizz1, resistin-like α (also called found in inflammatory zone 1, or Fizz1); SLC6A2, solute carrier family 6 member 2; Trem2, triggering receptor expressed on myeloid cells 2. From: Neuroimmune regulation of white adipose tissues, FEBS J. 2022 Dec;289(24):7830-7853 by Xinmin Qian et al. https://doi.org/10.1111/febs.16213
The CX3CR1+ population of macrophages is identified as sympathetic neuron-associated macrophages (SAMs). The authors discussed that a direct role of sympathetic regulation of macrophages has been postulated but remains to be fully illustrated. Macrophages express the adrenergic receptor β2 (Adrβ2); however, deletion of Adrβ2 driven by lyzM-Cre does not alter inflammation.
Overall, macrophages could adopt an immune phenotype across a wide spectrum in response to the external stimuli and metabolic states, which renders remarkable functional plasticity in influencing adipose biology. The authors concluded that the role of the peripheral innervation on adipose tissue metabolism becomes increasingly recognized, thus, unraveling a therapeutic opportunity to reshape the energy balance by modulating the neuronal pathways.
Moreover, they speculated that with the emerging evidence demonstrating the importance of individual cell types, collaborative research efforts on how the neuronal and immune components may interplay will provide invaluable knowledge to understand the systemic metabolism both at the organismal and cellular levels.
2024
Interestingly, another 2024 Japanese study disclosed a novel mechanism underlying the inhibitory effect of catecholamines, the end products of the sympathetic nervous system (SNS), on lipopolysaccharide (LPS)-induced inflammatory responses. Specifically, these investigators found that the β2-AR activation and protein kinase A (PKA) phosphorylation downregulated Toll-like receptor 4 (TLR4) expression in macrophages.
Of note, the authors discussed that their findings are consistent with those of previous studies, which demonstrated that catecholamines could decrease LPS-induced cytokine production in vitro and in vivo. The authors also reminded that, in patients with sepsis and septic shock, the two major catecholamines, noradrenaline, and adrenaline (in severe cases), are routinely administered as potent vasopressors for the treatment of hypotension and concomitant organ hypoperfusion.
Thus, the authors discussed that their results also suggest that the administration of catecholamines in emergency situations not only stabilizes circulatory dynamics but also suppresses the inflammatory response. Furthermore, the Japanese researchers found that the β2-AR activation could negatively regulate TLR4 expression. They also investigated the effect of PKA phosphorylation on TLR4 expression, and found that the activation of β2-AR stimulated PKA phosphorylation, which consequently downregulated TLR4 expression.
Thus, the authors concluded that their results suggest that SNS could regulate the inflammatory response, at least in part, via β2-AR/PKA-mediated TLR4 downregulation in macrophages.
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