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Biomarkers in Major Depression: Interleukin-33 (IL-33) & Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) (2024 Study)

Major depressive disorder (MDD) is a complex mental health condition that significantly impacts individuals’ lives globally.

A recent study evaluates the biological underpinnings of this disorder, focusing on two specific biomarkers: interleukin-33 (IL-33) and mesencephalic astrocyte-derived neurotrophic factor (MANF).

These findings could pave the way for new diagnostic and treatment strategies.


  • Major depressive disorder (MDD) affects millions worldwide, with symptoms persisting for weeks and impacting daily functioning.
  • Interleukin-33 (IL-33) and mesencephalic astrocyte-derived neurotrophic factor (MANF) are two biomarkers that have been linked to the pathophysiology of MDD.
  • The study found lower levels of IL-33 and higher levels of MANF in MDD patients compared to healthy controls.
  • These findings suggest the potential of IL-33 and MANF as biomarkers for MDD risk assessment and underscore the need for further research.

Source: BMC Psychiatry (2024)

Biological Roles of IL-33 & MANF and Alterations in Major Depression

IL-33: Role & Alteration in MDD

Biological Role

Interleukin-33 (IL-33) is an interleukin family member known for its dual function as a cytokine and a nuclear transcription regulator.

It plays a pivotal role in the immune response, particularly in the context of inflammation and allergy.

IL-33 is involved in promoting the production of Th2 cytokines and modulating the immune system’s response.

Alteration in MDD

In the context of Major Depressive Disorder (MDD), the observed lower levels of IL-33 could be indicative of disrupted immune regulation.

Depression has been associated with altered immune responses, including chronic low-grade inflammation.

The reduction in IL-33 levels in MDD patients might reflect an imbalance in inflammatory and anti-inflammatory mechanisms, potentially exacerbating depressive symptoms.

MANF: Role & Alteration in MDD

Biological Role

Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) is known for its role in cell survival and protection, particularly in neurons.

It has cytoprotective effects against endoplasmic reticulum (ER) stress and is involved in maintaining cellular homeostasis, particularly in the brain.

Alteration in MDD

The elevated levels of MANF found in MDD patients could be interpreted as a compensatory neuroprotective response to the cellular stress associated with depression.

This increase might represent an attempt by the body to counteract the negative effects of depression on neural health, such as oxidative stress or neuroinflammation.

IL-33 & MANF: Byproducts or Causes of Depression, or Both?

IL-33 & MANF as Byproducts of Depression

  • Reactive Changes: The changes in IL-33 and MANF levels in MDD patients could be a reaction to the physiological and psychological stressors associated with depression. Chronic stress, a common feature in depression, can trigger inflammatory responses and cellular stress mechanisms, potentially leading to alterations in these biomarkers.
  • Secondary Effects: It is also possible that these changes in IL-33 and MANF are secondary to other pathophysiological processes in MDD, such as neurotransmitter imbalances or HPA axis dysregulation.

IL-33 & MANF as Contributing Factors to Depression

  • Inflammatory Hypothesis: Given the role of IL-33 in immune regulation, its reduction might contribute to the pro-inflammatory state hypothesized in some forms of depression. This pro-inflammatory state could exacerbate or trigger depressive symptoms.
  • Neuroprotective Role of MANF: Conversely, the increase in MANF might initially be a protective response to counteract the neural damage associated with depression. However, if this response is inadequate or becomes dysregulated, it might contribute to the persistence or worsening of depressive symptoms.

Interplay of IL-33 & MANF in Depression

  • Bidirectional Relationship: The relationship between these biomarkers and depression is likely bidirectional. While depression might trigger changes in IL-33 and MANF levels, these alterations could, in turn, influence the severity and course of the disorder.
  • Complex Causality: The complexity of MDD suggests that IL-33 and MANF are part of a broader network of biological changes. They might both be affected by and contribute to the pathophysiology of depression, interacting with other factors like genetics, environmental stressors, and individual health conditions.

Serum Levels of IL-33 & MANF in Major Depression (2024 Study)

Nahar et al. conducted a study analyzing levels of IL-33 & MANF in patients with MDD – and findings were published in BMC Psychiatry (2024).

The primary objective of this research was to explore the potential roles of IL-33 and MANF in the pathophysiology of MDD.

By comparing the serum levels of these biomarkers in MDD patients and healthy controls, the study aimed to identify any significant differences that could contribute to understanding the biological basis of MDD.


  • Study Design and Participants: The study was a cross-sectional comparative analysis conducted from October to November 2022. It involved 129 MDD patients and 125 healthy controls (HCs), matched by sex and age. All participants were adults aged between 18 and 60 years.
  • Diagnostic Criteria and Severity Assessment: MDD patients were evaluated by a psychiatrist following the DSM-5 criteria. The Hamilton Depression Rating Scale (Ham-D) was used to assess the severity of the illness.
  • Biomarker Measurement: Serum concentrations of IL-33 and MANF were measured using enzyme-linked immunosorbent assay (ELISA) kits.


  • Serum IL-33 and MANF Levels: The study found that the mean serum levels of IL-33 were significantly lower in MDD patients (159.12 ± 6.07 pg/ml) compared to HCs (180.60 ± 8.64 pg/ml). Conversely, MANF levels were found to be significantly higher in MDD patients (5.40 ± 0.19 ng/ml) than in HCs (4.46 ± 0.21 ng/ml).
  • Sex-Specific Findings: Notable differences were observed in the serum levels of these biomarkers between male and female participants, suggesting potential sex differences in the biological underpinnings of MDD.
  • Association with Depression Severity: The study did not find a significant association between the severity of MDD (as measured by Ham-D scores) and the altered levels of IL-33 and MANF.


  • Scope of Biomarkers: The study focused only on IL-33 and MANF, which may not fully represent the complex neuroinflammatory processes involved in MDD.
  • Lifestyle and Treatment Factors: The effects of lifestyle, dietary habits, and existing treatments on the biomarkers were not accounted for in this study.
  • Longitudinal Changes: The study did not assess how these biomarker levels might change over time or in response to treatment for MDD.
  • Sample Size and Diversity: The study recommends further research with larger and more diverse sample sizes to validate and extend these findings.

Advanced Analysis of Results: IL-33 & MANF in Depressed Patients (2024)

Interpreting the Biomarker Variations

IL-33 Levels: The significant reduction in serum IL-33 levels in MDD patients compared to healthy controls is a critical finding. IL-33 is known for its role in immune response regulation and has been implicated in neuroinflammatory processes. Lower levels in MDD patients could indicate an altered immune response, potentially contributing to the pathophysiology of depression.

MANF Levels: The elevated MANF levels observed in MDD patients are equally intriguing. MANF is recognized for its neuroprotective and anti-inflammatory properties. Its increased levels might be a compensatory response to underlying neuroinflammatory processes in MDD, or it could represent a disrupted balance in neurotrophic support and stress response mechanisms.

Sex Differences: The sex-specific variations noted in biomarker levels could suggest differing pathophysiological mechanisms of MDD between males and females. (Higher IL-33 in females vs. males & higher MANF levels in males vs. females). This finding aligns with existing literature indicating gender differences in the prevalence and manifestation of depressive symptoms.

Correlation with Depression Severity

The absence of a direct correlation between the severity of depression (as measured by Ham-D scores) and the levels of IL-33 and MANF suggests that while these biomarkers may be associated with the presence of MDD, they may not reflect the severity of the condition.

This indicates the multifactorial nature of MDD, where multiple biological and environmental factors play a role.

Potential Implications of the Study (IL-33 & MANF in Depression)

Diagnostic & Therapeutic Implications

  • Biomarkers as Diagnostic Tools: The distinct differences in IL-33 and MANF levels between MDD patients and healthy individuals highlight their potential as biomarkers for MDD diagnosis. This could lead to more accurate and early detection of the disorder.
  • Personalized Medicine: Understanding the specific roles of these biomarkers could pave the way for personalized treatment approaches, tailoring interventions based on individual biomarker profiles.
  • Sex-Specific Treatments: The observed gender differences in biomarker levels could inform the development of gender-specific treatment strategies, addressing the unique biological underpinnings of MDD in men and women.

Public Health Perspective

  • Preventive Strategies: Identifying individuals at risk of developing MDD based on biomarker levels could enable early intervention and preventive strategies, potentially reducing the incidence and severity of the disorder.
  • Reducing the Stigma: The biological basis of MDD highlighted by these biomarkers could contribute to reducing the stigma associated with mental health disorders, emphasizing their physiological underpinnings.

Future Research of Depression Biomarkers (IL-33 & MANF)

  • Longitudinal Studies: Future studies should focus on longitudinal assessments to understand how IL-33 and MANF levels vary over time and in response to treatment.
  • Broader Biomarker Panels: Incorporating a wider range of biomarkers could provide a more comprehensive picture of the biological basis of MDD.
  • Diverse Populations: Research involving more diverse populations, including varying age groups, ethnicities, and socio-economic backgrounds, is crucial for generalizing the findings.
  • Combining Biological & Psychological Research: Integrating findings from biological research with psychological and social factors could lead to a more holistic understanding of MDD.
  • Collaborative Research Efforts: Collaborations between psychiatrists, neuroscientists, immunologists, and geneticists could yield deeper insights into the complex nature of MDD.
  • From Bench to Bedside: Translating these research findings into clinical practice is crucial. This includes developing clinical trials to test new diagnostic tools and treatments based on IL-33 and MANF.

Strategies to Normalize IL-33 & MANF Levels in Depression (Ideas)

Normalizing IL-33 and MANF levels in individuals with Major Depressive Disorder (MDD) involves a multifaceted approach that addresses both the biological and psychological aspects of the disorder.

Talk to a medical doctor before trying any intervention targeting IL-33 and MANF to ensure safety.

Here are several strategies that could potentially be effective:

Pharmacological Interventions

  • Anti-inflammatory Medications: Given the role of IL-33 in inflammation, medications with anti-inflammatory properties might help in normalizing its levels. These could include non-steroidal anti-inflammatory drugs (NSAIDs) or newer, more targeted anti-inflammatory agents.
  • Neuroprotective Agents: Drugs that enhance neuroprotection could be beneficial in normalizing MANF levels. These might include agents that reduce endoplasmic reticulum stress or enhance cellular resilience to stress.
  • Modulation of Neurotransmitter Systems: Antidepressants, especially those targeting serotonergic and noradrenergic systems, might indirectly influence the levels of IL-33 and MANF by alleviating the stress and inflammation associated with depression.

Lifestyle Modifications

  • Regular Exercise: Physical activity has been shown to have anti-inflammatory effects and could be beneficial in normalizing IL-33 levels. Exercise also promotes neurogenesis and the release of endogenous neurotrophic factors, potentially influencing MANF levels.
  • Dietary Changes: A diet rich in anti-inflammatory components, such as omega-3 fatty acids, and antioxidants may help in reducing inflammation and thus normalizing IL-33 levels. A balanced diet also supports overall brain health, which could be beneficial for MANF regulation.
  • Stress Reduction Techniques: Mindfulness, yoga, and other stress-reduction techniques can decrease the body’s stress response, potentially normalizing IL-33 and MANF levels. These practices also promote overall mental health and resilience.

Psychotherapeutic Interventions

  • Cognitive Behavioral Therapy (CBT): CBT and other forms of psychotherapy can help manage the psychological aspects of depression, potentially reducing the stress that may be contributing to altered IL-33 and MANF levels.
  • Mindfulness-Based Stress Reduction (MBSR): MBSR and similar programs can help individuals manage stress, which might be a factor in the dysregulation of these biomarkers.

Experimental & Emerging Therapies

  • Cytokine Therapy: Directly targeting cytokines through therapeutic interventions could be a novel approach. However, this is still in the experimental stage and requires more research.
  • Gene Therapy: If specific genetic factors are found to influence IL-33 and MANF levels, gene therapy could be a future avenue for normalizing these biomarkers.

Integrative Approaches

  • Combination Therapy: A combination of pharmacological treatments, lifestyle modifications, and psychotherapy may offer the best approach to normalizing IL-33 and MANF levels in MDD patients.
  • Personalized Medicine: Tailoring treatment strategies based on individual biomarker profiles, including IL-33 and MANF levels, could enhance the effectiveness of interventions.

Monitoring & Adjusting Treatment

  • Regular Biomarker Monitoring: Regularly monitoring IL-33 and MANF levels in patients could help in adjusting treatment plans as needed and assessing the effectiveness of different strategies.

These strategies underscore the importance of a comprehensive and individualized approach to treating depression, taking into account both the biological underpinnings and psychological aspects of the disorder.

Further research is needed to understand the precise mechanisms by which these strategies might affect IL-33 and MANF levels and their efficacy in treating MDD.


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