Apigenin, a natural flavonoid, attenuates EAE severity through modulation of dendritic
and other immune cell functions
Rashida
Emily
1*
McTish ,
2
Singh ,
Narendra
Chander
Pooja Jain1#, and Zafar K. Khan1#
3
Raman ,
Mitzi
2
Nagarkatti ,
of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, 2900 W
Queen Lane, PA, USA
2Department of Pathology, Microbiology and Immunology, University of South Carolina, Columbia, SC, USA
3Division of Clinical Immunology and Rheumatology, University of Alabama School of Medicine, 1825 University Boulevard, Birmingham, AB, USA
*Equal Contributions #Corresponding Authors
ABSTRACT
Apigenin, a natural flavonoid, found in parsley, chamomile and other plants, fruits,
vegetables, herbs, and spices is known to have anti-oxidant and anti-inflammatory
properties. The use of Apigenin containing plants for centuries as medicinal approaches to
treat asthma, intransigent insomnia, Parkinson's disease, neuralgia, and shingles have been
indicative of its role in the regulation of inflammation. However, there is a considerable
dearth of information regarding its effect on immune cells, especially dendritic cells (DC)
that maintain the critical balance between an immunogenic and tolerogenic immune
response, in an immunospecialized location like the central nervous system (CNS). Thus
we looked at the anti-inflammatory properties of Apigenin in restoration of immune
function and the resultant decrease in neuroinflammation. In vitro, Apigenin inhibited
IL-6 and TNF-α secretion in mouse monocyte-derived MDDCs and splenic DCs
stimulated with LPS and the cell surface expression of α4 integrin (adhesion), CD86 (costimulation), CLEC12A (antigen uptake) and MHC II (antigen presentation) molecules on
DCs. To test if Apigenin treatment ameliorates disease after onset of experimental
autoimmune encephalomyelitis (EAE) and its relapse, C57BL/6 and SJL mouse models of
multiple sclerosis were immunized with MOG35-55 and PLP139-151 respectively, followed
by treatment with Apigenin. A significant reduction in severity of EAE progression and
relapse was observed in the treated mice. Apigenin treated EAE mice show decreased
expression of α4 integrin and CLEC12A on splenic DCs and an increased retention of
DCs and macrophages in the periphery compared to untreated EAE mice. This correlated
with immunohistochemistry findings of decreased immune cell infiltration and reduced
demyelination in the CNS. These results indicate a protective role of Apigenin against the
neurodegenerative effects resulting from the entry of DC stimulated pathogenic T cells
into the CNS. Apigenin can thus serve as a potential therapy for neuroinflammatory
disease through its regulation of immunogenic T cell response.
Apigenin delays the course and attenuates EAE disease
severity
Restoration of immune cell function with Apigenin treatment
Integrins and lectins on DCs are down-modulated
in both C57BL/6 and SJL mice with Apigenin treatment
Apigenin reduces immune cell infiltration into the CNS
Apigenin sequesters immune cells in the spleen of both C57BL/6
and SJL mice
4x
Cervical
Lumbar
EAE + Vehicle
1Department
1*
Ginwala ,
INTRODUCTION
EAE + Apigenin
DCs and other immune cells in neuroinflammation and
the restoration of their function by Apigenin
HYPOTHESIS
EAE + Apigenin
EAE + Vehicle
4x
Accumulation of immune cells in the periphery of SJL mice upon
Apigenin treatment
Apigenin may target the pro-inflammatory functions of
DCs and their migration into the CNS, preventing
generation and activation of myelin-specific T cells
thereby reducing the marked neuroinflammation and its
associated clinical pathologies.
CONCLUSIONS AND FUTURE DIRECTIONS
Decreased TH17 response upon restimulation with
MOG and PLP peptides in Apigenin treated mice
Experimental autoimmune encephalomyelitis (EAE), a
well-established mouse model for neuroinflammation
representing multiple sclerosis (MS) in human
Apigenin restores immune cell function in treated EAE mice
Activation and co-stimulatory markers on DCs are
down-modulated in both C57BL/6 and SJL mice
with Apigenin treatment