The Role Of Th17 Cells/IL-17A in AD, PD, ALS And The Strategic Therapy Targeting On IL-17A Part 3

BBB disruption

In PD patients, the disruption of BBB was reported [122], and the increased permeabilization of BBB allowed the infltration of peripheral immune cells into the CNS [129]. In PD animal models, BBB was disrupted and the IL-17A level was increased in the SN [68].

The central nervous system is an important control center of the human body. It is responsible for controlling and regulating various functions of the body, such as breathing, heartbeat, digestion, etc. In addition, it also plays an important role and is closely related to human memory.

The brain of the central nervous system consists of two hemispheres, each responsible for different functions. The left brain is mainly responsible for activities such as language and logical thinking, while the right brain is responsible for activities such as space, creativity, and imagination. If the connection between the two hemispheres is not smooth, various neurological diseases will occur, such as memory loss, cognitive impairment, and other symptoms.

Memory is the most important one of human cognitive functions, and the central nervous system plays a vital role in it. The hippocampus in the brain is an area closely related to the processes of memory formation, storage, cognition, and retrieval. It can encode, store, and maintain detailed information such as sensory information, situations, and language in daily life to form long-term memory.

In addition, the primary visual cortex, temporal lobe, amygdala, etc. are also inseparable from the memory function of the central nervous system. If the functions of these areas are abnormal, it will affect people's memory, which may lead to a lack of self-cognition and identity.

Studies have shown that exercising the central nervous system can effectively enhance memory. For example, cognitive training, language games, immersive learning, and other activities can stimulate brain activity and strengthen the connection between neurons, thereby improving human memory and learning ability. Proper rest and sleep can also help restore and improve the brain's memory function.

In short, the central nervous system is the basis of human memory, and the protection and exercise of its function are very important. As long as we always pay attention to our memory health and improve the vitality of the brain through active cognition, learning, rest, and other methods, we will be able to maintain a good memory and lay a solid foundation for our future. It can be seen that we need to improve our memory, and Cistanche can significantly improve our memory because Cistanche has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of the neural network. These effects can help improve memory, learning ability, and thinking speed, and can also prevent the occurrence of cognitive dysfunction and neurodegenerative diseases.

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Systemic neuroinflammation

Previous studies had found increased circulating T17 cells in PD patients at the early stages of the disease [84, 104], indicating an important role of T17-driven inflammation in PD. '

Furthermore, in Porphyromonas gingivalis (Pg)-treated leucine-rich repeat kinase 2 (LRRK2) R1441G mice, dopaminergic neurons in the SN were reduced, but serum IL-17A, brain IL-17 receptor A, and activated microglial cells were increased; these findings indicated that neuroinflammation might play an important role in the pathophysiology of LRRK2-associated PD [130]. 

A previous study showed that auricular vagus nerve stimulation (aVNS) treatment decreased T17 cells, and reduced the levels of inflammatory cytokines, including TNF-α and IL-1β in 6-OHDA treats rats, indicating that aVNS could suppress the evolution of inflammation and modulate innate immune responses to play a neuroprotective role against dopaminergic damage [131]. 

In PD mice, administration of purified bee venom (BV) phospholipase A2 (bvPLA2) inhibited the loss of dopaminergic neurons within the SN in a dose-dependent manner, and this concentration-dependent action appeared to be related to the inhibition of T17 polarization; these results suggest that standardized bvPLA2 may have a neuroprotective effect against PD through neuroinflammation modulation [132]. 

JKAP, the regulator of immunity and inflammation, was also found to be correlated with T17 cells and disease severity in PD [133]. Repetitive transcranial magnetic stimulation (rTMS) was proved to have therapeutic effects on neuroinflammation via reducing the production of pro-inflammatory cytokines IFNγ and IL-17A [134].

Microglia activation

The addition of IL-17A to co-cultures of microglia and neurons led to the activation of microglia cells and TH+neuronal cell death. Interestingly, IL-17A exacerbated dopaminergic neuronal loss only in the presence of microglia. 

Furthermore, the inhibition of the IL-17A receptor on microglia was sufficient to attenuate these effects [68]. A network of communication may exist between glial cells and T17 cells, a greater understanding of this interaction may provide a novel therapeutic approach [135]. 

A previous study found that High mobility group protein B1 (HMGB1) A box inhibited the activation of microglia-mediated by HMGB1, inhibited the infiltration of T17 cells, and decreased the proportion of T17 in CD4+ T cells, indicating that HMGB1 A box may play a different role in protecting neurons in PD via influencing the activation of microglia cells, the infiltration of T17 cells, and the differentiation of T cells to T17 [136].

Alteration of gut microbiota

Altered gut microbiota was described in PD patients, and it also had a strong potential to mediate motor defects and neuroinflammation in the PD model [137]. Furthermore, intestinal microbiota can induce T17 differentiation [37]. 

Therefore, the specific T17 cells and their role in directing against gut microbiota might inspire the development of gut immunomodulatory therapeutic approaches in PD patients [129].

Strategic therapy targeting IL‑17A

In the experimental phase, the anti-T17 therapeutics in PD can be achieved by using nuclear receptor agonists, including peroxisome proliferator-activated receptor gamma (PPARγ) and liver X receptor (LXR), both of which are known to negatively regulate differentiation of T17 cells [138, 139]. 

These agonists may have therapeutic prospects in PD because they effectively inhibit PD pathology [140]. Furthermore, an anti-IL-17A-neutralizing antibody proved to be effective in alleviating the PD manifestations in the PD rat model [68].

Th17 cells and IL‑17A in ALS

ALS is a neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons (MNs), resulting in muscle weakness and paralysis. 

The possible involvement of T17 in ALS is indicated by circumstantial evidence. Studies have shown increased IL-17 levels in serum and CSF of ALS patients, and in the cell model, the IL-17 production was upregulated by cultured peripheral blood mononuclear cells [141, 142]. 

ALS patients had a higher expression of IL-17A in serum than controls, indicating a greater vulnerability of ALS patients to IL-17A-mediated damage. 

In ALS patients, the immune profile in peripheral blood was shifted towards a T1/T17 cell-mediated pro-inflammatory immune response, and T1 and T17 cells were moderately negatively correlated with disease severity, evaluated by forced vital capacity and ALS functional rating scale revised (ALSFRS-R) [143]. 

The spinal cords of ALS patients were found to be infiltrated by IL-17A-positive CD8 cells and IL-17A-positive mast cells. Mononuclear cells treated with aggregated superoxide dismutase-1 (SOD-1) protein could induce the expression of IL-6, IL-23, and IL-1β, which may be responsible for the induction of IL-17A [144]. 

IL-17A may be involved in chronic inflammation in ALS and could be a new therapeutic approach by immune modulation of inflammatory cytokines.

Strategic therapy targeting IL‑17A

A recent study developed a co-culture system of human induced pluripotent stem cells (hiPSCs)-derived MNs and T17 cells, derived from ALS patients, MS patients, and healthy controls. 

They found that T17 cells from MS patients induced severe degeneration of MNs, and IL-17A yielded a decline of viability and neurite length of MNs in a dose-dependent manner. Furthermore, neutralizing IL-17A and anti-IL-17A receptor treatment reverted this detrimental effect of IL-17A [143].

Conclusions

In 2021, we compared 761 age–gender-matched healthy controls with 761 PD patients and found that the ratio of CD4/CD8 in PD patients was higher than that in healthy controls, and the percentage of CD4+ T cells was negatively correlated with the Hoehn and Yahr (H&Y) stage [145]. 

However, we did not compare the subtypes of CD4+ T cells. 

Although the function of TH17/IL-17A on AD or PD is still contradictory and the mechanism of TH17/IL-17A is still unclear, the results of the latest research on IL-17A targeted treatments are still valid, so the pathogenesis and targeted therapy of IL-17A in neurodegenerative diseases are still worth exploring.

Abbreviations

AD: Alzheimer's disease; PD: Parkinson's disease; ALS: Amyotrophic lateral sclerosis; CNS: Central nervous system; TH17: T helper 17; IL-17A: Interleukin-17A; TGF-β: Transforming growth factor-β; ROR: Retinoic orphan receptor; CTLA: Cytotoxic T-lymphocyte antigen; TCR: T-cell receptor; NKT: Natural killer T; ILC3: Group 3 innate lymphoid cells; CXCL: C-X-C motif ligand; G-CSF: Granulocyte colony-stimulating factor; AS: Ankylosing spondylitis; RA: Rheumatoid arthritis; SLE: Systemic lupus erythematosus; IBD: Infammatory bowel disease; MS: Multiple sclerosis; EAE: Experimental autoimmune encephalomyelitis; CSF: The cerebral fuid; BBB: The blood–brain barrier; Aβ: Amyloid-β; FTD: Frontotemporal lobar degeneration; APP/PS1: Amyloid precursor protein/presenilin1; LPS: Lipopolysaccharide; Tg: Transgenic; SAL: Salidroside; SAMP8: Senescenceaccelerated mouse prone 8; TJ: Tight junctions; GM-CSF: Granulocyte macrophage-colony stimulating factor; TNF-α: Tumor necrosis factor-alpha; IFN-γ: Interferon-gamma; SD: Sprague-Dawley; JNK: C-Jun N-terminal kinase; JKAP: C-Jun N-terminal kinase (JNK) pathway-associated phosphatase; GAA: Acid alpha-glucosidase; BACE1: Beta-site APP-cleaving enzyme 1; DA: Dopaminergic; SNpc: Substantia nigra pars compacta; MPTP: Mitochondrial permeability transition pore; SN: Substantia nigra; REXO-C/ANP/S: Rabies virus glycoprotein (RVG) peptide-modifed exosome (EXO) curcumin/phenylboronic acid-poly(2- (dimethylamino)ethyl acrylate) nanoparticle/small interfering RNA targeting SNCA; DRD2: Dopamine 2 receptor; NFκB: Nuclear factor-kappa-B; LFA-1/ ICAM-1: Lymphocyte function-associated antigen-1/intercellular adhesion molecule-1; Pg: Porphyromonas gingivalis; LRRK2: Leucine-rich repeat kinase 2; aVNS: Auricular vagus nerve stimulation; bvPLA2: Bee venom (BV) phospholipase A2; rTMS: Repetitive transcranial magnetic stimulation; HMGB1: High mobility group protein B1; PPARγ: Peroxisome proliferator-activated receptor gamma; LXR: Liver X receptor; MNs: Motor neurons; ALSFRS-R: Amyotrophic lateral sclerosis functional rating scale revised; SOD-1: Superoxide dismutase.

Acknowledgments

Thank the authors of the references

Author contributions

All authors participated in drafting the article or revising it critically for important intellectual content. All authors read and approved the final manuscript.

Funding

This study was supported by a grant from the National Key Research and development program of China (Grant No. 2017YFC09007703), a grant from a science and technology planning project in Sichuan Province (Grant No. 2020YJ0281), a grant from 1·3·5 project for disciplines of excellence West China Hospital Sichuan University (Grant No. ZYJC18038), and the grant from cadres health care project in Sichuan Province (Grant No. 2019-112).

Availability of data and materials

No.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors agreed to be published.

Competing interests

The authors declare no competing interests.

Author Details

The author details 1 Department of Neurology, West China Hospital, Sichuan University, Wai Nan Guo Xue Xiang 37#, Chengdu, Sichuan, China. 2 Management Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. 3 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China. 4 Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.

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