Neuron︱Gang Cao's research group reveals a new mechanism by which the nervous system senses pathogenic infection and fine-tunes immune response

Written by ︱ Yu Jinsong, Xiao Ke, Cao Gang Editor ︱ Wang Sizhen An important advantage of biological evolution from unicellular organisms to multicellular organisms is that different types of cells or organs can divide labor and cooperate, and "communicate" in different ways, so as to be more efficient complete complex physiological tasks
.

Among them, the interaction between the nervous system and the immune system has received great attention in recent years.
The interaction and regulation of the nervous system and the immune system have become an important entry point for in-depth research on the regulation mechanism of the immune system under physiological and pathological conditions[1-4]
.

The immunomodulatory functions of specific nervous systems are very likely to provide new therapeutic ideas for the treatment of various immune diseases
.

But how does the nervous system sense pathogenic infections and immune responses? How to "communicate" with the immune system to fine-tune the immune response? Is the language of "communication" between these neuro-immune systems evolutionarily conserved? These issues are still poorly understood so far, greatly limiting the understanding of neuroimmune regulatory mechanisms, and hindering the development and application of therapeutic strategies for related diseases (eg, inflammatory storms, autoimmune diseases)
.

 On February 8, 2022, Professor Cao Gang's research group from Huazhong Agricultural University published an article "Neuron-derived neuropeptide Y fine-tunes the splenic immune responses" in Neuron, finding that the nervous system senses pathogenic infection, up-regulates neuropeptide NPY gene expression, and fine-tunes the splenic immune responses.
The new mechanism of regulating the body's immune response revealed that neurogenic NPY/F is an "ancient language" that mediates the communication between the nervous system and the immune system
.

The research was praised by reviewers as "tour de force" (a French loanword in English, meaning an exceptional achievement by an artist)
.

In this study, the neural pathway from the suprarenal-celiac ganglion (SrG-CG) to the spleen was first verified by retrograde tracing of pseudorabies virus
.

The RNA-seq analysis of SrG-CG revealed that rat SrG-CG was rich in NPY+ neurons
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And NPY was the gene with the most significant change in response to LPS treatment among all neurotransmitters
.

Subsequently, the researchers found that lipopolysaccharide (LPS) could directly activate SrG-CG neurons through calcium imaging experiments, and the expression of LPS receptor TLR4 and NPY in rat SrG-CG neurons co-localized
.

These results show that LPS can directly activate the adrenal-celiac ganglia and upregulate the expression level of NPY, a process that may play an important role in regulating the spleen immune response (Fig.
1)
.

Figure 1 LPS activates SrG-CG ganglia and induces the expression of NPY gene (Source: Yu J, et al.
, Neuron.
2022) To further study the immunoregulatory effect of NPY secreted by SrG-CG neurons on the spleen, researchers An adeno-associated virus with knockdown of NPY was constructed, and it was found that after knockdown of NPY in SrG-CG neurons, the functions of T cells, B cells and macrophages in the spleen were changed
.

scRNA-seq sequencing analysis and immunohistochemistry results showed that T cells and macrophages contain abundant NPY receptor NPY1R, which can directly communicate with NPY, but B cells do not have NPY1R
.

At the same time, the effect of NPY on macrophages can inhibit the TNF signaling pathway of macrophages and reduce the content of IL-1β, TNF-α and other cytokines in spleen macrophages
.

In order to further explain the function of SrG-CG NPY+ neurons when the body encounters systemic inflammation, splenocytes were stimulated by NPY in vitro, SrG-CG neurons were co-cultured with splenocytes, and NPY knockdown and overexpression experiments of SrG-CG neurons in vivo were performed.
, the researchers found that in the LPS-induced rat inflammation model, NPY in SrG-CG neurons mainly expressed the function of inhibiting the inflammatory storm in the spleen
.

 NPY is highly conserved during species evolution, and researchers speculate that the role of NPY in immune regulation is also highly likely to be conserved
.

The study found that neurogenic NPF (NPY homologue) in Drosophila has similar functions to rat NPY, and can significantly reduce the levels of antimicrobial peptides and cytokines induced by bacterial infection in Drosophila
.

This shows that the regulation of NPY on the immune system is evolutionarily conserved.
The communication between the nervous system and the immune system is a common feature of lower animals to higher animals, and neuropeptides (such as NPY, etc.
) are the maintenance of this communication.
ancient language
.

 NPY plays an important role in the immune regulation of the body, so are they related to the occurrence and development of human autoimmune diseases? Through the analysis of blood samples from patients with autoimmune diseases (such as rheumatoid arthritis, lupus erythematosus, etc.
), it was found that the content of NPY protein in the serum of patients with autoimmune diseases was significantly reduced
.

To further explore the relationship between NPY and autoimmune diseases, the researchers constructed a mouse arthritis model and found that knocking down the NPY level of SrG-CG aggravated the symptoms of arthritis in mice (Figure 2)
.

Therefore, peripheral neurotransmitter disorders (such as NPY) may be one of the reasons for the occurrence of autoimmune diseases.
Using NPY+ neurons as new drug targets or developing related short peptide drugs may be new ideas for the treatment of autoimmune diseases
.

Figure 2 The role of NPY in inhibiting autoimmune diseases (Source: Yu J, et al.
, Neuron.
2022) Conclusions and discussions, inspiration and prospects F is an ancient language for "communication" between the nervous system and the immune system.
It is conserved from fruit flies, mice, rats to humans.
The nervous system can sense pathogenic infection and upregulate the NPY expression of SrG-CG in large quantities.
Fine regulation of immune responses (Figure 2)
.

NPY/F may be used to alleviate the inflammatory storm caused during infection and regulate the immune balance in autoimmune diseases, and provide new ideas for the development of new drug targets and short peptide drugs for autoimmune diseases
.

However, the study leaves some unanswered scientific questions
.

For example, is there a co-regulation relationship between neurotransmitters such as norepinephrine and neuropeptide Y in the body, and what co-regulation mechanism is used to regulate the body's immune response? It is worth mentioning that the sensitivity of spleen immune cells to stimulation with different concentrations of NPY is not the same
.

How the body can precisely regulate the immune response through stimulation with different concentrations of norepinephrine and neuropeptide Y remains to be further studied
.

Link to the original text: https://doi.
org/10.
1016/j.
neuron.
2022.
01.
010 Professor Cao Gang from Huazhong Agricultural University is the corresponding author of this paper, and doctoral students Yu Jinsong and Dr.
Xiao Ke are the co-first authors of this research.
It also received strong support from Dr.
Dai Jinxia from Huazhong Agricultural University, Professor Hu Ji from Shanghai University of Science and Technology, Professor Guo Zheng from Tongji Medical College of Huazhong University of Science and Technology, Dr.
Chen Xiaohua from Wuhan Central Theater General Hospital and Professor Ma Qiufu from Harvard Medical School
.

This research was supported by the National Key R&D Program, the National Natural Science Foundation of China, the Special Funds for the Fundamental Research Funds of the Central Universities and the China Postdoctoral Science Foundation
.

Prof.
Cao Gang (first from left), Yu Jinsong (second from left), Dr.
Xiao Ke (first from right) (photo courtesy of Cao Gang's research group) Introduction to the corresponding author: Cao Gang, professor of Huazhong Agricultural University, doctoral supervisor
.

He has been engaged in the development of emerging omics technologies for a long time, such as (single-cell) spatial omics, (single-cell) three-dimensional genomics, (single-cell) connectomics and interaction omics technology development and its application in the "neuro-immune-infection" system applications in biological research
.

In the past 5 years, the laboratory has published many papers in journals such as Nature Genetics, Neuron, Science Advance, Nucleic Acids Res, Nature Communication, Science Bulletin, Molecular Neurodegeneration, GPB, etc.
, and obtained many patents
.

 The research team is conducting further research work on the integration of multi-dimensional in situ sequencing spatial omics and connectomics and its application in "neuro-immune-infection" systems biology research and "in vitro diagnostics".
Interested parties are welcome.
Graduate students and postdocs join! Please contact by email: gcao@mail.
hzau.
edu.
cn Selected articles from previous issues [1] J Neuroinflammation︱Ge Jinfang/Xia Qingrong's research group reveals the partial therapeutic mechanism of bone marrow mesenchymal stem cell exosomes on Alzheimer's disease[1] 2] Sci Transl Med︱GABAB receptor may save visual processing abnormalities in autistic patients [3] Sci Adv︱ Xu Yong/Xu Wenping/He Yanlin collaborated to discover the neural circuit mechanism of estrogen receptor neurons regulating body temperature and movement 【4】PNAS︱Chun Han’s group reveals a new mechanism of neuronal degeneration caused by external phagocytosis 【5】Nat Neurosci︱VTA dopaminergic neurons are involved in encoding social prediction error and social reinforcement learning 【6】Nature︱New discovery! Inflammatory lymphocytes or new targets mediating CNS inflammation? 【7】Neurosci Bull︱Hu Bo’s research group reveals that the deep cerebellar nucleus neurons projecting to the ventromedial thalamus are specifically involved in the regulation of combined sensory-motor learning behavior 【8】Nat Neurosci︱Wu Longjun’s research group reveals the key pathological proteins of ALS The new ligand of TDP-43——TREM2【9】Cereb Cortex︱Luo Yuejia’s team revealed the cognitive control mechanism under the condition of uncertain expectation in anxious individuals 【10】PNAS︱Xiao Bo’s research group revealed a new mechanism for regulating the development of myelin in the central nervous system Mechanism references (swipe up and down to view) 1.
Chavan, SS, Ma, P.
& Chiu, IM Neuro-immune interactions in inflammation and host defense: Implications for transplantation.
American Journal of Transplantation (2017).
2.
Okusa, M.
, Rosin, D.
& Tracey, K.