GDF-15 recombinant protein: A key regulatory factor from pregnancy-induced immune tolerance to neuroprotection in multiple sclerosis

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This article focuses on the molecular characteristics and neuroimmunomodulatory functions of growth differentiation factor 15 (GDF-15), systematically elaborating the association between elevated GDF-15 levels during pregnancy and reduced relapse rates in multiple sclerosis. It analyzes the molecular mechanism by which GDF-15 activates the "brain-spleen axis" sympathetic nerve signaling through the brainstem GFRAL receptor, thereby inhibiting the migration of autoreactive T cells. Additionally, it explores the therapeutic potential of GDF-15 recombinant protein in neuroinflammatory interventions.

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GDF-15 Recombinant Protein: A Key Regulatory Factor from Pregnancy-Induced Immune Tolerance to Neuroprotection in Multiple Sclerosis

Summary: This article systematically elaborates on the molecular characteristics and neuroimmune regulatory functions of Growth Differentiation Factor 15 (GDF-15), exploring its association between elevated levels during pregnancy and reduced relapse rates in multiple sclerosis. It analyzes the molecular mechanism by which GDF-15 activates the "brain-spleen axis" sympathetic nerve signaling through the brainstem GFRAL receptor, inhibiting the migration of autoreactive T cells, and discusses the therapeutic potential of GDF-15 recombinant protein in neuroinflammatory interventions.

1. Disease Characteristics of Multiple Sclerosis and Pregnancy-Induced Protective Phenomena

Multiple sclerosis is caused by autoimmune dysregulation in the central nervous system, leading to demyelination and neurodegenerative lesions. During pregnancy, inflammatory activity in patients decreases, but known pregnancy hormones cannot fully replicate this protective effect. Growth Differentiation Factor 15 increases with fetal development during pregnancy and is associated with fetal immune tolerance. Its receptor, GFRAL, is primarily expressed in brainstem neurons. Previous studies have focused on the metabolic functions of GDF-15, while its role in neuroinflammation remains unclear. This study aims to explore the regulation of autoreactive T cells by the GDF-15/GFRAL axis and its significance in neuroinflammation. This research background raises a key question: Is the elevated GDF-15 during pregnancy the critical molecule mediating the protective effects of pregnancy in MS?

2. Expression Characteristics of GDF-15 and Its Association with Neuroinflammation

GDF-15 is significantly elevated during pregnancy, particularly in semi-allogeneic pregnancies. Clinical data show that human serum GDF-15 levels increase with gestational age, with lower levels in women who miscarry compared to those who undergo elective abortions. MS patients with pregnancy relapses exhibit significantly lower early GDF-15 levels. These clinical associations suggest a close relationship between GDF-15 levels and both pregnancy maintenance and MS disease activity.

Under conditions of central nervous system inflammation, GDF-15 expression is markedly induced. During the acute phase of EAE (an animal model of MS), Gdf15 expression in the spinal cord is significantly higher than in the cortex. Neurons, astrocytes, and infiltrating myeloid cells are the primary sources of GDF-15. Functional necessity studies reveal that Gdf15 knockout mice exhibit reduced EAE survival rates, increased clinical scores, and pro-inflammatory microglial phenotypes. These findings establish the endogenous protective role of GDF-15 in neuroinflammation.

3. Therapeutic Anti-Neuroinflammatory Effects of GDF-15 Delivery

Neuron-targeted delivery of GDF-15 or administration of recombinant GDF-15 significantly suppresses neuroinflammation in EAE models, reducing immune cell infiltration in the central nervous system independently of caloric restriction. In gene therapy experiments, AAV-mediated neuronal overexpression of GDF-15 lowers EAE clinical scores, decreases macrophage and T cell infiltration in the central nervous system, and reduces the fluorescence intensity of the microglial activation marker Iba1.

In recombinant protein validation experiments, subcutaneous injection of recombinant human GDF-15 alleviates EAE symptoms without weight loss and reduces Iba1 activity in spinal cord white matter. Paired feeding experiments confirm that the anti-inflammatory effects of GDF-15 are independent of caloric restriction. This finding has significant translational implications—systemic administration of recombinant GDF-15 protein achieves neuroprotective effects without complex gene therapy procedures, offering a more convenient pathway for clinical translation.

4. Regulatory Mechanisms of GDF-15 on Autoreactive T Cells

GDF-15 downregulates T cell surface integrins, inhibits activation and proliferation, and reduces their migration to the central nervous system. At the peripheral immune regulation level, GDF-15 overexpression significantly decreases leukocyte and T cell counts in the spleen and inguinal lymph nodes, downregulating the expression of LFA-1 (high-affinity conformation), CD29, and CD49d on CD4+ T cells. These integrin molecules are essential for T cell migration across the blood-brain barrier, and their downregulation directly impairs T cell migration to the central nervous system.

In terms of T cell functional inhibition, during the preclinical phase of EAE, GDF-15 overexpression reduces the expression of CD4+ T cell activation marker Nur77, proliferation marker Ki67, and memory marker CD44, with decreased TNF secretion upon antigen restimulation. These data indicate that GDF-15 not only reduces T cell numbers but also functionally suppresses their activation and effector functions.

5. Molecular Mechanisms Mediated by β-Adrenergic Signaling

GDF-15 activates splenic sympathetic nerves through GFRAL, promoting norepinephrine release, which binds to the β2 adrenergic receptors on CD4+ T cells, thereby inhibiting T cell function. In terms of metabolism and neural activation, GDF-15 overexpression alters plasma lipid profiles, increases splenic tyrosine hydroxylase expression, and elevates norepinephrine levels. Tyrosine hydroxylase is the rate-limiting enzyme in norepinephrine synthesis, and its increased expression indicates enhanced sympathetic nerve activity.

At the direct T cell regulation level, norepinephrine or epinephrine treatment inhibits CD4+ T cell proliferation, CD44 expression, and LFA-1 levels, with β2 receptor inhibitors reversing these effects. Adrb2 knockout completely blocks norepinephrine-mediated CD69 downregulation. These experimental findings comprehensively reveal the signaling cascade from GDF-15 to GFRAL neurons, sympathetic nerves, and T cells.

6. GFRAL Dependency and Neuron-Specific Regulation

The anti-inflammatory effects of GDF-15 depend on neuronal GFRAL, and direct activation of GFRAL+ neurons can replicate these effects. In GFRAL dependency validation, GDF-15 mutants (unable to bind GFRAL) or Gfral knockout mice show no anti-inflammatory effects, with no increase in splenic tyrosine hydroxylase expression or norepinephrine levels, and restored LFA-1 expression on central nervous system T cells. GFRAL reporter mice confirm its exclusive expression in brainstem area postrema and nucleus tractus solitarius neurons.

In chemogenetic activation experiments, DREADD-mediated activation of GFRAL+ neurons induces weight loss, significantly alleviates EAE clinical symptoms, reduces immune cell infiltration in the central nervous system, increases splenic tyrosine hydroxylase expression and norepinephrine levels, and downregulates T cell LFA-1. This experiment demonstrates that direct activation of GFRAL+ neurons can mimic the neuroprotective effects of GDF-15.

7. Integrated Mechanism Model and Research Application Value of GDF-15 Recombinant Protein

The study outlines a clear working model: signal source (pregnancy, inflammation, or therapeutic GDF-15) → central perception (brainstem GFRAL+ neurons) → neural output (activation of sympathetic "brain-spleen axis") → peripheral effects (splenic norepinephrine release) → target cell action (inhibition of CD4+ T cell LFA-1 and activation via β2 adrenergic receptors) → final outcome (prevention of T cell infiltration into the central nervous system and alleviation of neuroinflammation). This model comprehensively describes the functional cascade from GDF-15 molecules to neuroimmune regulation.

8. Conclusion

GDF-15, as a key molecule elevated during pregnancy and associated with reduced relapse rates in multiple sclerosis, binds to the GFRAL receptor on brainstem neurons, activating splenic β-adrenergic signaling and norepinephrine synthesis. This downregulates integrins required for T cell migration across the blood-brain barrier, inhibiting the activation and migration of autoreactive T cells and alleviating neuroinflammation. Therapeutic strategies targeting this axis show significant effects in MS animal models, providing a new target direction for MS treatment. The GDF-15/MIC-1 Protein, Mouse provided by U-Antibody offers reliable tool support for in-depth analysis of the neuroimmune regulatory mechanisms of the GDF-15/GFRAL axis and the development of targeted therapeutic strategies, continuing to drive profound exploration in the field of neuroimmunology.

This article is reviewed and published by the technical expert team of UA

Disclaimer: This article partially utilizes artificial intelligence assistance in its creation. If any content involves copyright or intellectual property issues, please let us know and we promise to verify and remove it as soon as possible.

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