Periodic Reporting for period 4 - NEURIMMUNE (Neural regulation of immunity)
Reporting period: 2020-04-01 to 2021-09-30
The survival of living organisms depends on their capacity to mount a defense against environmental agents that cause tissue damage and infection. Traditionally, the activity of the immune system in repairing tissue injury and combating pathogens has been considered quite different from that of the nervous system, which transduces environmental or internal damaging signals into electrical activity to produce reflexes and sensations. However, anatomical and cellular bases for bidirectional interactions between these two systems have been established. The aim of the NeurImmune project was to investigate how neural and immune signals are interconnected and integrated to shape the host response to pathogens and injuries.
Stress can be defined as a state of altered homeostasis resulting from external or internal stimuli, including inflammatory processes, infections and pain. In response to these stimuli, various adaptive neuroendocrine mechanisms are induced to restore homeostasis. Part of this response is initiated within the central nervous system and translated into action by the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system. We found that these neuroendocrine pathways modulate inflammatory and immune responses to viruses and bacterial products.
In addition, sensory nerves are stimulated when an injury, an infection or an inflammation occurs in tissues, including the skin. These neurons convey the damaging information to the brain (inducing pain) and release a number of mediators and neuropeptides in situ that can modulate the function of immune cells locally. We identified and characterized new regulatory mechanisms affecting the immune response by investigating the functional role of the nervous system in immunity.
Stress can be defined as a state of altered homeostasis resulting from external or internal stimuli, including inflammatory processes, infections and pain. In response to these stimuli, various adaptive neuroendocrine mechanisms are induced to restore homeostasis. Part of this response is initiated within the central nervous system and translated into action by the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system. We found that these neuroendocrine pathways modulate inflammatory and immune responses to viruses and bacterial products.
In addition, sensory nerves are stimulated when an injury, an infection or an inflammation occurs in tissues, including the skin. These neurons convey the damaging information to the brain (inducing pain) and release a number of mediators and neuropeptides in situ that can modulate the function of immune cells locally. We identified and characterized new regulatory mechanisms affecting the immune response by investigating the functional role of the nervous system in immunity.
We analyzed the role of neuroendocrine pathways in regulating immune responses. Our studies were divided in two main parts:
1) Role of sensory neurons in regulating skin immune response upon injury or infection.
Nociceptors are primary sensory neurons that detect noxious stimuli and inform the brain of the occurrence of infectious, inflammatory or damaging processes. All tissues highly exposed to the external environment, such as the epithelial surfaces of the skin, are densely innervated by nociceptors. These sensory neurons can release some neuropeptides which can attract or activate immune cells (mast cells, dendritic cells).
We analyzed the role played by nociceptors in the activation and recruitment of innate immune cells in the skin after tissue damage or viral infection, and in the generation of adaptive immune responses. In particular, we used several genetic mouse models in which the innervation of the skin by primary sensory neurons is defective. These mice have impaired sensitivity to injury and inflammation-induced pain and are valuable tools for investigating the role of sensory nerves in the immune response in vivo.
We monitored the impact of the lack of skin innervation by nociceptive sensory neurons on the activation and recruitment of immune cells in the skin and cutaneous lymph node (LN) of mice after UV-induced tissue damage and HSV-1 infection (Filtjens et al. 2021; Hoeffel et al. 2021).
We found that these neurons are important for the regulation of inflammation by controlling both innate and adaptive immune responses. We have also identified a major role of TAFA4, a molecule produced by a subset of sensory neurons, in regulating skin inflammation and promoting tissue repair after skin overexposure to UV-light.
More precisely, tissue-resident macrophages have a key role in tissue repair, but the precise molecular mechanisms that regulate the balance between inflammatory and pro-repair macrophage responses during healing remain poorly understood. We demonstrated a major role for sensory neurons in promoting the tissue-repair function of macrophages. In a sunburn-like model of skin damage in mice, the conditional ablation of sensory neurons expressing the Gαi-interacting protein (GINIP) results in defective tissue regeneration and in dermal fibrosis (Hoeffel et al 2021). Elucidation of the underlying molecular mechanisms revealed a crucial role for the neuropeptide TAFA4, which is produced in the skin by C-low threshold mechanoreceptors—a subset of GINIP+ neurons. TAFA4 modulates the inflammatory profile of macrophages directly in vitro. In vivo studies in Tafa4-deficient mice revealed that TAFA4 promotes the production of IL-10 by dermal macrophages after UV-induced skin damage. This TAFA4–IL-10 axis also ensures the survival and maintenance of IL-10+TIM4+ dermal macrophages, reducing skin inflammation and promoting tissue regeneration. These results reveal a neuroimmune regulatory pathway driven by the neuropeptide TAFA4 that promotes the anti-inflammatory functions of macrophages and prevents fibrosis after tissue damage (Hoeffel et al. 2021), and could lead to new therapeutic perspectives for inflammatory diseases.
2) Role of the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS) on the regulation of tissue-specific inflammatory responses.
Following stress, infection or inflammation, stimulation of the HPA axis and the sympathetic nervous system (SNS) induces the adrenal gland to release epinephrine and glucocorticoids into the bloodstream. Nerve fibers from the SNS also release the neurotransmitter norepinephrine into lymphoid organs and tissues. These mediators can stimulate adrenergic receptors (AR) and glucocorticoid receptors (GR) on leukocytes. We studied the role of these receptors in Natural killer (NK) cells, innate lymphoid cells (ILCs) and myeloid cells. We have shown that host resistance to endotoxic shock and viral infection requires the neuroendocrine regulation of NK cells through the glucocorticoid receptor (Quatrini at al. 2017, Quatrini at al. 2018) revealing a novel strategy of host protection from immunopathology. We also found that 2-adrenergic pathways are detrimental for host resistance to viral infection (Wieduwild et al. 2020).
Our results show that the immune response is regulated by mediators produced by the nervous system. The data obtained in the frame of the NeurImmune study will enable us to propose new innovative therapeutic strategies (3 patent applications).
1) Role of sensory neurons in regulating skin immune response upon injury or infection.
Nociceptors are primary sensory neurons that detect noxious stimuli and inform the brain of the occurrence of infectious, inflammatory or damaging processes. All tissues highly exposed to the external environment, such as the epithelial surfaces of the skin, are densely innervated by nociceptors. These sensory neurons can release some neuropeptides which can attract or activate immune cells (mast cells, dendritic cells).
We analyzed the role played by nociceptors in the activation and recruitment of innate immune cells in the skin after tissue damage or viral infection, and in the generation of adaptive immune responses. In particular, we used several genetic mouse models in which the innervation of the skin by primary sensory neurons is defective. These mice have impaired sensitivity to injury and inflammation-induced pain and are valuable tools for investigating the role of sensory nerves in the immune response in vivo.
We monitored the impact of the lack of skin innervation by nociceptive sensory neurons on the activation and recruitment of immune cells in the skin and cutaneous lymph node (LN) of mice after UV-induced tissue damage and HSV-1 infection (Filtjens et al. 2021; Hoeffel et al. 2021).
We found that these neurons are important for the regulation of inflammation by controlling both innate and adaptive immune responses. We have also identified a major role of TAFA4, a molecule produced by a subset of sensory neurons, in regulating skin inflammation and promoting tissue repair after skin overexposure to UV-light.
More precisely, tissue-resident macrophages have a key role in tissue repair, but the precise molecular mechanisms that regulate the balance between inflammatory and pro-repair macrophage responses during healing remain poorly understood. We demonstrated a major role for sensory neurons in promoting the tissue-repair function of macrophages. In a sunburn-like model of skin damage in mice, the conditional ablation of sensory neurons expressing the Gαi-interacting protein (GINIP) results in defective tissue regeneration and in dermal fibrosis (Hoeffel et al 2021). Elucidation of the underlying molecular mechanisms revealed a crucial role for the neuropeptide TAFA4, which is produced in the skin by C-low threshold mechanoreceptors—a subset of GINIP+ neurons. TAFA4 modulates the inflammatory profile of macrophages directly in vitro. In vivo studies in Tafa4-deficient mice revealed that TAFA4 promotes the production of IL-10 by dermal macrophages after UV-induced skin damage. This TAFA4–IL-10 axis also ensures the survival and maintenance of IL-10+TIM4+ dermal macrophages, reducing skin inflammation and promoting tissue regeneration. These results reveal a neuroimmune regulatory pathway driven by the neuropeptide TAFA4 that promotes the anti-inflammatory functions of macrophages and prevents fibrosis after tissue damage (Hoeffel et al. 2021), and could lead to new therapeutic perspectives for inflammatory diseases.
2) Role of the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS) on the regulation of tissue-specific inflammatory responses.
Following stress, infection or inflammation, stimulation of the HPA axis and the sympathetic nervous system (SNS) induces the adrenal gland to release epinephrine and glucocorticoids into the bloodstream. Nerve fibers from the SNS also release the neurotransmitter norepinephrine into lymphoid organs and tissues. These mediators can stimulate adrenergic receptors (AR) and glucocorticoid receptors (GR) on leukocytes. We studied the role of these receptors in Natural killer (NK) cells, innate lymphoid cells (ILCs) and myeloid cells. We have shown that host resistance to endotoxic shock and viral infection requires the neuroendocrine regulation of NK cells through the glucocorticoid receptor (Quatrini at al. 2017, Quatrini at al. 2018) revealing a novel strategy of host protection from immunopathology. We also found that 2-adrenergic pathways are detrimental for host resistance to viral infection (Wieduwild et al. 2020).
Our results show that the immune response is regulated by mediators produced by the nervous system. The data obtained in the frame of the NeurImmune study will enable us to propose new innovative therapeutic strategies (3 patent applications).
Our studies provided unexpected and new insight into the mechanisms by which the nervous and immune systems cooperate to ensure a controlled and appropriate response to pathological challenges, to restore homeostasis. They should open new fields of investigation.