After encountering specific pathogens, the innate immune system will promote the development of naive CD4⁺ T cells into effector Th cells, which are fundamental regulators of adaptive immunity. Different subtypes of CD4⁺ Th cells are distinguished according to cytokines, transcription factors, and effector immune regulatory functions. Initially, activated CD4⁺ Th cells were frequently differentiated into one of two fates: Th1 or Th2 cells. Th1 cells, generating interleukin (IL)-2, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α), mainly take part in delayed-type hypersensitivity reactions and cell-mediated immune responses, such as autoimmune disorders. Th2 cells, renowned for their generation of the cytokine IL-4, mediate host defense against helminths and link with the pathogenesis of allergic diseases. In 2005, a newly identified subtype of CD4⁺ Th cells, so-called Th17 cells, was discovered that represent a diverse population, which underwent differentiation in the presence of transforming growth factor-beta (TGF-β) and IL-6 (16, 17). Now, it was recognized that Th17 cells might be more significant than Th1 cells in the development of some models of autoimmune illness, including PD, AD, MS, ALS, and MDD (5–7).

Th17 cells perform crucial roles in pro-inflammatory properties, inflammation, and essential tasks to defend the host against extracellular bacterial and fungal infections. Th17 cells are defined as CD4⁺ Th lymphocytes that secrete large amounts of IL-17A and express the transcription factor retinoic acid-related orphan receptor gamma-T (RORγt), which possibly acts as a molecular determinant for their polarization (18, 19). Th17 cells have two most distinct characteristics: strong plasticity and prominent capability to boost other immune cells (e.g., Th1 cells, neutrophils, and immunosuppressive head box P3 Treg cells).

Initially, the differentiation of Th17 cells was shown to be induced by the combination of IL-6 and TGF-β (20). Subsequently, Korn and colleagues found that IL-21, which was induced by signal transducer and activator of transcription 3 (STAT3)/IL-6 signaling, could affect Th17 cell development and response amplification (21). IL-21 acts in a loop of autocrine amplification to culminate in the differentiation and proliferation of Th17 cells and the production of the IL-23 receptor (IL-23R). IL-23 plays a key role in the late growth and maturation of Th17 cells by activating its receptor IL-23R via IL-6 and/or IL-21 ( Figure 1 ) (22). Additionally, Th17 cells differentiated in the IL-1⁺/IL-23⁺/TGF-β⁻ environment show greater encephalitogenic activity after adoptive transfer, which highlights the importance of IL-23 and IL-1 in the differentiation and pathogenicity of Th17 cells (23). Nonetheless, IFN-γ (Th1 cytokine) and IL-4 (Th2 cytokine) can inhibit the differentiation of Th17 cells from naive CD4⁺ Th cells as long as the Th17 cells have not been fully developed (24, 25).

RORγt, which was encoded by the RORC gene and generally expressed in Th17 cells, is the major regulator of the Th17 cell differentiation. Rorc knockout mice cannot produce Th17 cells (26). Meanwhile, overexpression of RORγt, triggered by the activity of IL-6 and TGF-β, can lead to Th1- and Th2-independent differentiation of naive CD4⁺ Th cell progenitors into the Th17 subtype (27, 28). Moreover, RORγt may cooperate with other transcription factors during the differentiation of Th17 cells (29). When activated by IL-6, IL-21, or IL-23, STAT3 is the upregulator of RORγt in response to TGF-β and IL-6. STAT3 can bind to plenty of Th17-related loci and is essential for the induction of the Th17 transcriptional program (30). In the absence of STAT3, overexpression of RORγt cannot restore Th17 cell development (31). Numerous essential transcription factors, such as STAT5, granulocyte monocyte-colony stimulating factor (GM-CSF), aryl hydrocarbon receptor (Ahr), activating transcription factor-like runt-related transcription factor-1 (RUNX1), transcriptional coactivator with postsynaptic density 65-discs large-zonal occluder 1-binding motif (TAZ), and interferon regulatory factor 4 (IRF4), regulate Th17 cell differentiation (29, 32, 33). Th17 cells are regarded as strongly pathogenic because they drive autoinflammation by producing a unique set of cytokines (e.g., IL-17A, IL-21, IL-23, IL-6, IFN-γ, and GM-CSF) ( Figure 1 ).

It has been shown that IL-17A, mainly produced by Th17 cells, can induce cytokine secretion and has functions in immune inflammation (34). Numerous studies signify that IL-17A, stimulating glial cells and enhancing neuroinflammatory responses, performs a pathogenic role in the CNS (35, 36). IL-17 signaling also induces the activation of NF-κB cascade response to control the corresponding physiological function (37).

Increasing evidence indicates that multiple environmental factors will contribute to the development of NDs. It is not difficult to think that different host environmental factors may also accelerate the pathogenic potential of Th17 cells and that immune responses may promote autoimmunity, therefore causing NDs.

PD, the second most prevalent form of neurodegenerative disease, is characterized by motor symptoms, such as tremors, rigidity, and bradykinesia (66). In PD, there is a progressive degeneration of neurons in various regions of the brain, including dopaminergic neurons in the substantia nigra pars compacta (67). A critical pathological hallmark of PD is the accumulation of αSyn (so-called Lewy bodies). In addition to protein aggregation, inflammatory responses play a crucial role in the etiology and pathogenesis of PD, as evidenced by the elevated expression of IFN-γ, IL-17A, and IL-6 in the brain (68). PD patients also have a disruption of BBB, which allows peripheral immune cells to infiltrate into the brain and potentially influences other mechanistic pathways associated with neurodegeneration, such as oxidative stress and mitochondrial dysfunction potentially (68). Therefore, the enhanced peripheral inflammation may initiate or exacerbate PD pathology. Recently, Sommer et al. provided direct evidence that the neurotoxic effect of Th17 cells, expanded in an autocrine loop, was increased in PD patients (69). This model also revealed a direct contact between Th17 cells and neurons leading to dopaminergic neuronal apoptosis. In a mouse model with a deficiency of IL-17A, motor impairment, dopaminergic neurodegeneration, and BBB disruption were alleviated (70). Furthermore, Gate and colleagues provided the exact mechanism for Th17 cell-mediated dopaminergic neuron death via secretion of IL-17A in PD (71). Th17 cells secrete pro-inflammatory cytokines that were associated with the activation of other detrimental inflammatory factors (like TNF-α, IL-1β, and IL-6), which were released from brain microglial cells (the most numerous types of brain cell). Ultimately, Th17 cells and inflammatory factors promote inflammatory reactions and neuronal apoptosis ( Figure 2 ). On the other hand, abnormally accumulated αSyn becomes an autoimmune antigen that activates microglia into the microglia type 1 subtype, which promotes the differentiation of Th17 subtypes and activates intracellular inflammatory pathways (72). Although the direct effects of Th17 cells on neurons have been described in these studies, additional work is still needed to comprehend the activity of PD-related Th17 neurotoxicity in a more complex intracellular environment to open up novel therapeutic development avenues.

AD is the most frequent form of late-onset dementia and has progressive and irreversible pathogenesis with a complex molecular disease etiology, which affects over 40 million people worldwide (73). AD is a multifactorial neurological disorder, in which the extracellular deposits of amyloid β (Aβ) peptides and fibrillary tangles of intraneuronal hyperphosphorylated tau protein are the major histopathological hallmarks. Aβ is obtained by the frequent and serial activation of the γ-secretase enzymes and β-secretase 1 (BACE1) on a larger precursor protein (APP) (74). Highly insoluble Aβ peptides are considered an important factor in AD pathogenesis. They motivate the microglia to secrete pro-inflammatory cytokines and chemokines to activate the complement pathway (75), thus inducing the cumulation of inflammatory cells into the CNS that leads to neurodegeneration (76). Indeed, Aβ peptides have been shown to enhance the manufacture of reactive oxygen species (ROS) and nitric oxide (NO) by microglia, leading to OxS development and stimulating the inflammation of the Th17/IL-17A axis, and then impair microglia-mediated Aβ phagocytosis and contribute to Aβ accumulation and neuronal damage. Additionally, the primary roles of IL-17A in the pathogenesis of AD are to attract neutrophils and then stimulate their function. Zenaro et al. showed that Aβ aggregates could mediate the recruitment and chemotaxis of neutrophils to produce IL-17A, which is directly toxic to neurons and the BBB and may amplify neutrophils in the CNS, thus contributing to a vicious circle that leads to exacerbating pathology (77). Since neutrophils are the primary targets and crucial sources of IL-17A in the CNS, they may play a significant role in the development of AD pathology by promoting inflammation and neuron autophagy. The presence of extremely high levels of IL-17A, TNF-α, IL-2, and GM-CSF in the brain of a triple transgenic mouse model of AD indicates that neurodegeneration in these mice is related to Th17 polarization. Another study found a notable increase of IL-17A, RORγt, and IL-22 in the serum, hippocampus, and CSF of Aβ-42 peptide-injected rats (78). In addition, Tian et al. indicated a correlation between postoperative cognitive impairment and elevated levels of IL-17A in the hippocampus (79). Recently, a study has reported that the administration of blocking anti-IL-17A antibodies could rescue Aβ-induced cognitive impairment and neuroinflammation (80). These findings provide evidence for the synergistic roles of Th17 cells and their associated cytokines in promoting neuroinflammation and degeneration in AD.

The number of CD4⁺ and CD8⁺ T cells in AD patients’ brain parenchyma and vascular endothelium is significantly higher than normal (81). The activated Th17 cells and their inflammatory cytokines (e.g., IL-17A, IL-21, and IL-23) in the brain may jointly promote AD neuropathology (82). Furthermore, a number of studies found that AD patients had elevated levels of the Th17 transcription factor RORγt in their lymphocytes (83, 84). Recently, other studies have demonstrated the relationship between Th17 cells and early AD (85). Therefore, some scholars proposed that the optimal AD vaccine should inhibit Th17 immune responses to Aβ to prevent neuroinflammation and subsequent neurodegeneration (86).

MS is a widespread demyelinating disease of the CNS resulting in substantial neurological disability, in which immune cells and related cytokines are involved in the degradation of myelin sheaths (87). Inflammatory processes in these foci led to myelin damage and oligodendrocyte rupture, followed by axonal loss and transient or permanent loss of neurologic functions, resulting in varying degrees of disability (88). Until now, the pathophysiology of MS has not been elucidated clearly. Still, the prevailing view of MS pathogenesis is the breach of immunological tolerance and the active infiltration of myelin antigen-sensitive immune cells into brain tissue through the BBB. Emerging data from clinical and animal studies have revealed that myelin-specific immune cells (such as B cells, Th1 cells, and Th17 cells) are activated in lymph organs of the periphery. These myelin-specific immune cells develop encephalitogenic potential and infiltrate the CNS, where they are reactivated and expanded by the IL-23 and IL-1β (produced by resident microglia and infiltrating inflammatory monocytes) (62, 89). Furthermore, multiple studies have indicated that Th1 and Th17 cells are enhanced in the brain parenchyma in the acute phase of MS patients (90, 91). Th17 cells mainly cause brain damage, but Th1 cells induce spinal cord inflammation. In the attempt to clarify the role of Th1 and Th17 cells in the pathogenesis of MS, Langrish et al. showed that Th17 cells induce more severe experimental autoimmune encephalomyelitis (EAE) than Th1 cells (92). Th17 cells, especially Th1-like Th17 cells, may participate in EAE pathology by producing IFN-γ and IL-17A. Th17 cells result in oligodendrocyte death, axonal degeneration, and neuronal dysfunction (91, 93). Multiple studies in various EAEs, animal models of MS, have demonstrated that Th1-like Th17 cells can across the BBB by stimulating the IL-17A and C-C chemokine receptor 6 (CCK6) and enhance neuroinflammation (87, 94, 95). In the CSF and peripheral blood of patients with MS relapse, Durelli and colleagues detected that a higher IL-17A expression was positively associated with disease activity (96). Mice that lack Th17 and its characteristic cytokines, including IL-23, IL-21, and IL-22, are also at risk of developing EAE (97, 98). Furthermore, Hartlehnert and colleagues identified the induction of the B-cell-supporting meningeal microenvironment by Bcl6 in Th17 cells as a mechanism controlling neuroinflammation (99). Therefore, IL-17A and B cells have a considerable but non-essential function in EAE. Additionally, mice lacking RORγt, a crucial transcription factor for Th17 differentiation, exhibit a delayed onset or mild progression of EAE (100). Unlike other Th17 cytokines, GM-CSF, regulated by IL-23, RORγt, and IL-1β, has an encephalitogenic profile and a non-redundant role in active myeloid cell infiltration leading to sustained neuroinflammation in MS (101). Although the absence of GM-CSF had no effect on Th cells infiltrating into the CNS, it severely inhibited the accumulation of tissue-invading phagocytes, which are the primary drivers of immunopathology and are capable of initiating tissue damage (101). Consequently, Th17 cells and their related factors have a significant role in the pathogenesis of MS.

ALS is a progressive neurodegenerative disease, which is characterized by the clustering and accumulation of ubiquitylated, proteinaceous inclusions in the upper and lower motoneurons (MN), resulting in dramatic muscle paralysis, extramotor abnormalities, or death (102). Although the pathophysiological mechanisms of ALS are still unresolved, multiple studies corroborated that the pathological processes of ALS are involved in neuroinflammation, mainly attributed to the activation of CNS innate immune cells, and may precede MN cell death (35, 103). Neuroinflammation in ALS is characterized by the accumulation of massive astrocytes and activated microglia, which increases the production of potentially cytotoxic molecules (such as ROS, inflammatory mediators, and pro-inflammatory cytokines) (104). Interestingly, recent studies provide evidence that Th17 cells and their associated cytokines (e.g., IL-17A, TNF-α, IFN-γ) are enhanced in the CSF, peripheral blood, and serum of ALS patients (35, 104). In clinical studies with ALS, Meng et al. showed that peripheral pro-inflammatory Th17 cell shift was linked to disease severity (13). These findings proved that therapeutic interventions on Th17 cells and/or their cytokines may be a promising treatment strategy in ALS patients.

MDD is one of the most commonly recognized mental disorders globally. The number of patients receiving antidepressant treatment is increasing yearly, which is a severe medical, social, and economic problem. According to the Composite International Diagnostic Interview version of the World Mental Health Survey, MDD is a chronic psychiatric disorder with long-term depressive symptoms (e.g., anxiety, loss of pleasure, and low sense of self-worth). With the steadily rising number of young patients with MDD over the past decade, there is an urgent need for more effective therapeutic strategies and the identification of the molecular mechanisms underlying chronic MDD. Although the etiology of MDD has yet to be determined, mounting evidence supports a link between depression and elevated levels of IL-17A, suggesting that inflammation exacerbates depressive symptoms. Indeed, numerous pro-inflammatory cytokines (e.g., IL-1β, IL-23, IFN-γ, and TNF-α) and Th17 cells are elevated in the peripheral blood of depressed patients (105, 106). Alvarez-Mon et al. clearly showed an increased propensity for Th17 differentiation in the circulating population of CD4⁺ T lymphocytes in adult patients with MDD (105). In addition, several studies have also demonstrated that Th17 cells were increased in the brains of the rodent models of MDD (107). Interestingly, studies showed that administration of Th17 cells would result in increased sensitivity to depression in two different mouse models, giving a direct correlation between Th17 cells and depression sensitivity (108, 109). The absence of RORγt and the neutralization of IL-17A both conferred resistance to the induction of learned helplessness in mice (108). Nevertheless, the levels of IL-17A are not always correlated with depression, and there is no evidence indicating that Th17 cells cause neuron damage in MDD. Similar to psoriasis and MS surveys, patients with rheumatoid arthritis who have elevated levels of IL-17A also have an increased risk of depression and anxiety disorders (110, 111). These findings suggest that Th17 cells may not be sufficient to cause depression on their own, but they have additional roles to promote depression. To clarify whether IL-17A is directly involved in neuroimmune interactions, further research is required.

IL-17A is the critical effector cytokine secreted by Th17 cells. Only three monoclonal antibodies of IL-17A and IL-17AR were approved, namely, secukinumab, ixekizumab, and brodalumab. Secukinumab is a fully human monoclonal antibody, which was labeled as first-line therapy for moderate to severe cases of active or stable psoriasis (122). Macaluso and colleagues first demonstrated secukinumab’s clinical efficacy on neurological manifestations in patients with concomitant ankylosing spondylitis (AS) and MS, supporting the fact that IL-17A blockade may become a potential therapeutic target in MS (112). Cortese et al. also suggested that secukinumab was efficacious for treating CNS demyelination in AS patients, but this topic still needs further studies (123). Moreover, the restoration of neuronal cell death produced by Th17 cells by secukinumab in PD patient-generated pluripotent stem cell-derived neurons motivated us to look for additional possible immunotherapies for PD (69). Ixekizumab, another human monoclonal antibody, inhibits the inflammatory response mediated by IL-17A binding to the IL-17A receptor (IL-17AR), whereas brodalumab can specifically block the IL-17 receptor. Extensive clinical studies have shown that ixekizumab and brodalumab are beneficial and used by the FDA in adults with moderate to severe plaque psoriasis (114, 124). Emerging evidence hints that the therapeutic interventions on IL-17A may be a promising treatment strategy in ND patients. To confirm the efficacy of anti-IL-17A/IL-17AR antibodies in the treatment of NDs, additional research is required.

In addition to IL-17A, Th17 cells release numerous additional cytokines, including GM-CSF, IL-23, and RORγt. GM-CSF was reported to play a pathogenic role in NDs, such as AD, PD, MS, and MDD. Several studies in AD and PD animal models have demonstrated that anti-GM-CSF antibodies would inhibit the activation of the microglia and astrocytes in the CNS, suggesting that it may be a potential therapeutic target (113, 115). In support of this finding, Manczak and colleagues observed that animals injected with anti-GM-CSF antibodies had decreased Aβ deposition and microglia expression (116). Since IL-23 and RORγt are involved in the differentiation and activation of Th17 cells, targeting the IL-23 or RORγt in the treatment of NDs is exciting and an effective approach (117). Currently, several RORγt inverse agonists, including oleanonic acid, ursolic acid, and TAK-828F, have been identified (118–120). For instance, SR1001 could alleviate the severity and delay the onset of EAE in distinct mechanisms, including limiting Th17 cell differentiation and reducing the expression of Th17 cytokines (117).