Participants studied herein is a subsample in the clinical trial, which demonstrated LBP treated youths with StD achieved accelerated recovery of depressive symptoms and higher remission rate as well as well-tolerance compared to placebo(13). Notwithstanding the small sample size in the current study, our major finding was that youths treated with LBP have an accelerated reduction in peripheral IL-17A. Moreover, those treated with LBP are more likely to exhibit a diminished correlation as well as connectivity of systemic cytokine expression.
IL-17A, commonly known as IL-17, is a pro-inflammatory cytokine, the most studied member of the IL-17 family (16), secreted mainly by Th17 cells but also by granulocytes, monocytes, and astrocytes, etc (17). The Th17 cell population is mainly located in the lamina propria of the small gut and is responsible for immune surveillance (18). Physiologically, Th17 cells and IL-17A are almost absent in other organs, and not detectable in the blood(19, 20). Elevated levels of Th17 cells and IL-17A in the CNS were related to increased neuroinflammation(17, 18), as seen in experimental autoimmune encephalomyelitis(21). Recently, the role of IL-17A in depression has been gaining emphasis(18). Previous cross-sectional studies found that patients who suffered from depression have elevated levels of Th17 and IL-17A(17). Preclinical studies proved that administration of IL-17A could produce depressive-like behaviors in mice model(22, 23), implying IL-17A involved in the pathophysiology of depression.
Despite increasing evidence assuming a certain role of IL-17A in depression of whatever kind, the pathological role of IL-17A on depression is still unclarity(18). It has been suggested that IL-17A impairs the brain-blood barrier integrity and activates astrocytes and microglia to induce the production of inflammatory mediators, such as intercellular adhesion molecule 1, prostaglandin E2, matrix metalloproteinases, other cytokines, and antimicrobial peptides to mediate neuroinflammation, which furtherly damage synaptic dysfunction in the hippocampus, amygdala, and prefrontal cortex(23-25). Induction and release of those mediators also appear to amplify IL-17A production through a positive feedback loop, thereby spreading inflammatory damage(26).
Furthermore, anti-IL-17 treatment may reduce neuroinflammatory response and possibly mediate antidepressant effects. In the current study, we found that LBP-treated youths with StD have an improvement in depressive symptoms accompanied by downregulation of the IL-17A level. This result is in accordance with a separate study with escitalopram which reported that the drug reduced the peripheral level of IL-17 during therapy(27). In addition, Kim and colleagues, recently, reported that administering anti-IL-17/IL-17A antibody by suppressing the action of IL-17 could improve depressive behavior in mice model(23). Of note, a longitudinal study that evaluated various cytokines during antidepressant therapy revealed that peripheral levels of IL-17A increased significantly in the non-responder group compared to the responder, implying that IL-17A may be a useful marker for non-responsiveness to antidepressant treatment(28). Given that, IL-17A could be a potential therapeutic target and treatment-responsive marker for depression.
Immunological processes are complexity and muti-regulated. It is necessary to consider not only a single cytokine of the inflammation system, but also their interaction in evaluating immune response(29). Cytokine signaling shows synergistic or antagonistic as to regulating growth and differentiation of immune cells. For example, IL-4 not only amplifies IL-3 for each other to induce differentiation, and activation of mast cells in a synergistic way, but also blocks the secretion of IL-12(30-32). In addition, the reaction of cytokine cascades plays a crucial role in cytokine signaling, meaning that activation of one cytokine induces an immune cell type to produce another cytokine(29). For example, if the T helper (TH0) cells produce IL-6, the consequence is activation of TH17 cells which secrete pro-inflammatory cytokines like IL-17, IL-21, and IL-22(33). Based on co-regulations and interactions between cytokines, utilizing network analysis to demonstrate connectivity and centrality of multiple inflammatory mediators has been proved to be useful in assessing the impact of anti-inflammatory therapeutics(9). In this study, we found LBP treatment reduced correlations and connectivity of cytokines in youths with StD when compared to the placebo-controlled group. This result suggested that LBP affects the peripheral inflammatory milieu altering the systemic cytokine network. In addition, our result supports the idea that anti-inflammatory agents that block the pathologic pathway of the immune response may have a vital role in the alleviation of depressive symptoms(34, 35).
Though the pharmacological pathway of LBP acting on the Central Nervous System is still not confirmed, it may be related to the microbiota-gut-brain (MGB) axis. Preclinical studies found LBP treated mice could improve lipid metabolism, and insulin levels accompanied by significantly decreased peripheral levels of TNF-α and IL-17A(36). They suggested that these positive effects of LBP are probably attributed to the function of the gut microbiota in upregulating host defense against infection after treatment. In addition, our preclinical study on the depressive mice model proved that administration of LBP could improve depressive-like behavior by preventing aberrant neuronal activity and microglial activation in the lateral habenula associated with reducing neuroinflammatory response(12). Based on the above-mentioned, we conjecture the anti-depressant effect of LBP may modulate inflammation response through the MGB axis. However, more studies will be needed to elucidate the mechanism of LBP on inflammation response and its causality with MGB and depression.
Several limitations need to be mentioned and its post hoc design. The strength of this study is hindered by the small sample size and distribution (80% were female) that impede the generalizability of the findings of this trial. In addition, we firstly utilized an undirected network to probe the pharmacological pathway of LBP acting on inflammatory cytokines. The specific inflammatory pathway and pharmacological mechanism influenced by LBP should be further clarified in future studies. Finally, peripheral levels of cytokines could be influenced by confounders, such as age, body mass index, and blood pressure, cytokine concentrations in the cerebrospinal fluid might better reflect cytokine signaling in the brain than levels of cytokine in the peripheral blood and should be applied in the future(29).
In conclusion, this study presented here offers innovative immunological insights that immune response is downregulated after repeated LBP administration, and such alterations were correlated with improvement of depressive symptoms. In addition, our findings suggest reshaping the inflammatory pathway may be involved in the antidepressant effects. Future studies are required to replicate and validate our findings.