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Published on: October 13, 2023
Pentraxin-3 is upregulated in the central nervous system during MS and EAE, but does not modulate experimental
Kimberley Ummenthum1, Laura A N Peferoen1, Annamaria Finardi2
1Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands.
Abstract:
Pentraxin-3 (PTX3), an acute-phase protein released during inflammation, aids phagocytic clearance of pathogens and apoptotic cells, and plays diverse immunoregulatory roles in tissue injury. In neuroinflammatory diseases, like MS, resident microglia could become activated by endogenous agonists for Toll like receptors (TLRs). Previously we showed a strong TLR2-mediated induction of PTX3 in cultured human microglia and macrophages by HspB5, which accumulates in glia during MS. Given the anti-inflammatory effects of HspB5, we examined the contribution of PTX3 to these effects in MS and its animal model EAE. Our data indicate that TLR engagement effectively induces PTX3 expression in human microglia, and that such expression is readily detectable in MS lesions. Enhanced PTX3 expression is prominently expressed in microglia in preactive MS lesions, and in microglia/macrophages engaged in myelin phagocytosis in actively demyelinating lesions. Yet, we did not detect PTX3 in cerebrospinal fluid of MS patients. PTX3 expression is also elevated in spinal cords during chronic relapsing EAE in Biozzi ABH mice, but the EAE severity and time course in PTX3-deficient mice did not differ from WT mice. Moreover, systemic PTX3 administration did not alter the disease onset or severity. Our findings reveal local functions of PTX3 during neuroinflammation in facilitating myelin phagocytosis, but do not point to a role for PTX3 in controlling the development of autoimmune neuroinflammation.
Insights
Pentraxin-3 (PTX3) aids myelin clearance in neuroinflammation but does not control autoimmune disease development. PTX3 is found in MS lesions, yet its absence or administration did not alter disease severity in mouse models.
Area of Science:
- Neuroimmunology
- Cellular and Molecular Immunology
Background:
- Pentraxin-3 (PTX3) is an acute-phase protein involved in inflammation and tissue repair.
- Microglia, the resident immune cells of the brain, play a key role in neuroinflammatory diseases like multiple sclerosis (MS).
- Toll-like receptors (TLRs) on microglia can be activated by endogenous molecules, influencing neuroinflammation.
Purpose of the Study:
- To investigate the role of PTX3 in the context of MS and its animal model, experimental autoimmune encephalomyelitis (EAE).
- To determine if PTX3 contributes to the anti-inflammatory effects of HspB5 in microglia.
- To assess the functional significance of PTX3 in the development and progression of autoimmune neuroinflammation.
Main Methods:
- Analysis of PTX3 expression in human microglia and macrophages stimulated via TLRs.
- Immunohistochemical examination of PTX3 localization in MS lesions and EAE spinal cords.
- Assessment of EAE severity and disease course in PTX3-deficient mice compared to wild-type (WT) mice.
- Evaluation of the effects of systemic PTX3 administration on EAE.
Main Results:
- TLR engagement robustly induces PTX3 expression in human microglia, which is detectable in MS lesions.
- PTX3 is prominently expressed by microglia in preactive MS lesions and by microglia/macrophages involved in myelin phagocytosis in active lesions.
- No significant difference in EAE severity or disease course was observed between PTX3-deficient and WT mice.
- Systemic PTX3 administration did not impact EAE onset or severity.
- PTX3 was not detected in the cerebrospinal fluid of MS patients.
Conclusions:
- PTX3 is locally expressed in microglia within MS lesions, particularly during myelin phagocytosis.
- While PTX3 facilitates myelin clearance, it does not appear to play a critical role in controlling the overall development or severity of autoimmune neuroinflammation.
- The study suggests localized functions for PTX3 in neuroinflammation rather than a systemic immunomodulatory role in MS pathogenesis.
