A sympathetic-eosinophil axis orchestrates psychological stress to exacerbate skin inflammation.
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| Title: | A sympathetic-eosinophil axis orchestrates psychological stress to exacerbate skin inflammation. |
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| Authors: | Tian, Jiahe (AUTHOR), Cao, Yudian (AUTHOR), Li, Yilei (AUTHOR), Sun, Junlong (AUTHOR), Zhan, Cheng (AUTHOR), Ni, Wei (AUTHOR), Zheng, Yongjun (AUTHOR), Wang, Yanqing (AUTHOR), Liu, Shenbin (AUTHOR) |
| Source: | Science. 3/19/2026, Vol. 391 Issue 6791, p1269-1277. 9p. |
| Subjects: | Eosinophils, Sympathetic nervous system, Beta adrenoceptors, Psychological stress, Neuroimmunology, Chemokine receptors, Atopic dermatitis, Skin inflammation |
| Abstract: | Psychological stress is believed to exacerbate dermatitis, yet the neurobiological mechanisms linking stress to immune processes remain elusive. We identified a subset of prodynorphin-positive (Pdyn+) noradrenergic sympathetic neurons in mice that specifically innervate hairy skin, mediating stress-induced exacerbation of skin inflammation in an eosinophil-dependent manner. Genetic ablation of Pdyn+ sympathetic neurons or eosinophils mitigated stress-evoked worsening of inflammation in atopic dermatitis–like mice, whereas optogenetic activation of these neurons precipitated inflammation through eosinophils. Pdyn+ sympathetic neurons recruited eosinophils through the CCL11-CCR3 axis and activated them through the adrenergic receptor beta2 (Adrb2) in inflamed skin. Our findings reveal a neuroimmunological mechanism underlying psychological stress–induced exacerbation of dermatitis, emphasizing the Pdyn+ sympathetic-eosinophil axis as a crucial interface between the brain and skin inflammation, with potential therapeutic implications. Editor's summary: Although psychological stress is thought to aggravate atopic dermatitis, the cellular and molecular mechanisms are not well established. Tian et al. performed a retrospective analysis of patients with this condition and found correlations between elevated stress and increased accumulation of eosinophils in the skin (see the Perspective by Gaudenzio and Basso). In mice, a distinct type of sympathetic neuron that innervated the skin relayed stress responses from the brain to eosinophils and exacerbated inflammation. These neurons released a chemokine, CCL11, that recruited eosinophils. The ability of eosinophils to promote stress-induced inflammation was dependent on their expression of the adrenergic receptor β2. These results suggest that, in combination with other treatments, managing stress or blocking stress-dependent signaling between neurons and eosinophils may help to alleviate dermatitis. —Sarah H. Ross INTRODUCTION: Psychological stress is a well-established exacerbating factor for atopic dermatitis (AD), capable of worsening inflammation through complex interactions among the nervous, endocrine, and immune systems. Stress hormones can directly compromise the skin barrier, promote inflammation, and intensify the sensation of itch. Scratching in response to itch further damages the skin, creating a self-perpetuating cycle of inflammation and psychological distress. Consequently, stress management is considered an integral component in the comprehensive management of AD. RATIONALE: Eosinophilic infiltration is a pathological hallmark of AD. Eosinophil-derived mediators, including granule proteins such as eosinophil peroxidase (Epx) and major basic protein (MBP), as well as cytokines such as interleukin-31 (IL-31), potently amplify inflammatory cascades and correlate with disease severity. The mechanistic basis governing eosinophil recruitment and activation specifically within the context of psychological stress remains poorly understood, representing a significant knowledge gap in cutaneous neuroimmune communications. Additionally, whereas sympathetic neurons exhibit target-specific organization and participate in peripheral immunomodulation during stress responses, the precise pathways through which psychological stress converges with atopy-associated inflammation remain incompletely delineated, particularly regarding their connection to eosinophil-mediated inflammation in stressed skin. RESULTS: To determine the immune mediators and neural pathways through which stress signals aggravate skin inflammation, we conducted a retrospective analysis of AD patients and studied stress-challenged murine AD models. Our analysis revealed a specific association between stress-induced eosinophilia and skin inflammation severity in AD patients. In mice, genetic ablation of eosinophils (in EpxiCre-DTA mice) conferred protection against stress-exacerbated dermatitis. Through chemical sympathectomy with 6-hydroxydopamine and surgical removal of the adrenal glands, we determined that peripheral sympathetic nerves, rather than the hypothalamus-pituitary-adrenal axis, mediates the stress-induced worsening of skin inflammation. Using single-nucleus RNA sequencing and intersectional genetic approaches, we further identified two major populations of noradrenergic sympathetic neurons in mice, defined by prodynorphin (Pdyn) and neuropeptide Y (Npy) expression, that were activated by psychological stress. Our functional studies suggested that skin-innervating Pdyn+ sympathetic neurons, but not their Npy+ counterparts, were both necessary and sufficient for driving stress-induced dermatitis and eosinophilia. Optogenetic activation of Pdyn+ neurons promoted eosinophil recruitment and exacerbated inflammation, effects that were abolished upon eosinophil depletion. These Pdyn+ neurons were found to release the chemokine C-C motif ligand 11 (CCL11), which acts on its receptor, C-C chemokine receptor type 3 (CCR3), to mediate eosinophil chemotaxis. Finally, adrenergic signaling through adrenergic receptor beta2 (Adrb2) on eosinophils was critical, because eosinophil-specific Adrb2 knockout mitigated stress-induced exacerbation of dermatitis. CONCLUSION: Our findings suggest that psychological stress exacerbates AD-like inflammation through a specialized subset of skin-innervating Pdyn+ noradrenergic sympathetic neurons that engage eosinophils through the CCL11-CCR3 chemotactic axis and Adrb2-mediated activation. These results indicate that stress-induced eosinophilia could be a potential biomarker of AD severity and suggest that targeting the Pdyn+ sympathetic neuron-eosinophil interface may offer therapeutic benefit in mitigating the inflammatory sequelae of psychological stress. Pdyn+ sympathetic neurons mediate psychological stress–evoked eosinophilia and dermatitis.: Skin-projecting Pdyn+ sympathetic (sym.) neurons, but not their Npy+ counterparts, orchestrate stress-aggravated dermatitis by recruiting eosinophils (Eos) through the CCL11-CCR3 axis. Additionally, these neurons release norepinephrine (NE), which activates eosinophils through Adrb2 receptors, triggering the release of cytotoxic granule proteins (e.g., Epx) and proinflammatory cytokines (e.g., IL-31) within the inflamed skin. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | Psychological stress is believed to exacerbate dermatitis, yet the neurobiological mechanisms linking stress to immune processes remain elusive. We identified a subset of prodynorphin-positive (Pdyn+) noradrenergic sympathetic neurons in mice that specifically innervate hairy skin, mediating stress-induced exacerbation of skin inflammation in an eosinophil-dependent manner. Genetic ablation of Pdyn+ sympathetic neurons or eosinophils mitigated stress-evoked worsening of inflammation in atopic dermatitis–like mice, whereas optogenetic activation of these neurons precipitated inflammation through eosinophils. Pdyn+ sympathetic neurons recruited eosinophils through the CCL11-CCR3 axis and activated them through the adrenergic receptor beta2 (Adrb2) in inflamed skin. Our findings reveal a neuroimmunological mechanism underlying psychological stress–induced exacerbation of dermatitis, emphasizing the Pdyn+ sympathetic-eosinophil axis as a crucial interface between the brain and skin inflammation, with potential therapeutic implications. Editor's summary: Although psychological stress is thought to aggravate atopic dermatitis, the cellular and molecular mechanisms are not well established. Tian et al. performed a retrospective analysis of patients with this condition and found correlations between elevated stress and increased accumulation of eosinophils in the skin (see the Perspective by Gaudenzio and Basso). In mice, a distinct type of sympathetic neuron that innervated the skin relayed stress responses from the brain to eosinophils and exacerbated inflammation. These neurons released a chemokine, CCL11, that recruited eosinophils. The ability of eosinophils to promote stress-induced inflammation was dependent on their expression of the adrenergic receptor β2. These results suggest that, in combination with other treatments, managing stress or blocking stress-dependent signaling between neurons and eosinophils may help to alleviate dermatitis. —Sarah H. Ross INTRODUCTION: Psychological stress is a well-established exacerbating factor for atopic dermatitis (AD), capable of worsening inflammation through complex interactions among the nervous, endocrine, and immune systems. Stress hormones can directly compromise the skin barrier, promote inflammation, and intensify the sensation of itch. Scratching in response to itch further damages the skin, creating a self-perpetuating cycle of inflammation and psychological distress. Consequently, stress management is considered an integral component in the comprehensive management of AD. RATIONALE: Eosinophilic infiltration is a pathological hallmark of AD. Eosinophil-derived mediators, including granule proteins such as eosinophil peroxidase (Epx) and major basic protein (MBP), as well as cytokines such as interleukin-31 (IL-31), potently amplify inflammatory cascades and correlate with disease severity. The mechanistic basis governing eosinophil recruitment and activation specifically within the context of psychological stress remains poorly understood, representing a significant knowledge gap in cutaneous neuroimmune communications. Additionally, whereas sympathetic neurons exhibit target-specific organization and participate in peripheral immunomodulation during stress responses, the precise pathways through which psychological stress converges with atopy-associated inflammation remain incompletely delineated, particularly regarding their connection to eosinophil-mediated inflammation in stressed skin. RESULTS: To determine the immune mediators and neural pathways through which stress signals aggravate skin inflammation, we conducted a retrospective analysis of AD patients and studied stress-challenged murine AD models. Our analysis revealed a specific association between stress-induced eosinophilia and skin inflammation severity in AD patients. In mice, genetic ablation of eosinophils (in EpxiCre-DTA mice) conferred protection against stress-exacerbated dermatitis. Through chemical sympathectomy with 6-hydroxydopamine and surgical removal of the adrenal glands, we determined that peripheral sympathetic nerves, rather than the hypothalamus-pituitary-adrenal axis, mediates the stress-induced worsening of skin inflammation. Using single-nucleus RNA sequencing and intersectional genetic approaches, we further identified two major populations of noradrenergic sympathetic neurons in mice, defined by prodynorphin (Pdyn) and neuropeptide Y (Npy) expression, that were activated by psychological stress. Our functional studies suggested that skin-innervating Pdyn+ sympathetic neurons, but not their Npy+ counterparts, were both necessary and sufficient for driving stress-induced dermatitis and eosinophilia. Optogenetic activation of Pdyn+ neurons promoted eosinophil recruitment and exacerbated inflammation, effects that were abolished upon eosinophil depletion. These Pdyn+ neurons were found to release the chemokine C-C motif ligand 11 (CCL11), which acts on its receptor, C-C chemokine receptor type 3 (CCR3), to mediate eosinophil chemotaxis. Finally, adrenergic signaling through adrenergic receptor beta2 (Adrb2) on eosinophils was critical, because eosinophil-specific Adrb2 knockout mitigated stress-induced exacerbation of dermatitis. CONCLUSION: Our findings suggest that psychological stress exacerbates AD-like inflammation through a specialized subset of skin-innervating Pdyn+ noradrenergic sympathetic neurons that engage eosinophils through the CCL11-CCR3 chemotactic axis and Adrb2-mediated activation. These results indicate that stress-induced eosinophilia could be a potential biomarker of AD severity and suggest that targeting the Pdyn+ sympathetic neuron-eosinophil interface may offer therapeutic benefit in mitigating the inflammatory sequelae of psychological stress. Pdyn+ sympathetic neurons mediate psychological stress–evoked eosinophilia and dermatitis.: Skin-projecting Pdyn+ sympathetic (sym.) neurons, but not their Npy+ counterparts, orchestrate stress-aggravated dermatitis by recruiting eosinophils (Eos) through the CCL11-CCR3 axis. Additionally, these neurons release norepinephrine (NE), which activates eosinophils through Adrb2 receptors, triggering the release of cytotoxic granule proteins (e.g., Epx) and proinflammatory cytokines (e.g., IL-31) within the inflamed skin. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adv5974 |
