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Activation of uterine innate immune system affects embryo im

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Javier Arturo Sánchez Jr.

on 25 June 2015

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Transcript of Activation of uterine innate immune system affects embryo im

Activation of uterine innate immune system affects embryo implantation and endometrial receptivity
Embryo implantation
Interaction between the blastocyst and endometrium epithelium.
Window of implantation. Late secretory phase. Between days LH+5 +7.
Guarantee the success of pregnancy.

Causes leading to infertility
Infections STD:
Chlamydia
Trichomonas
HPV

PID
Endometriosis
Cancer
Javier Arturo Sánchez-López
AURDM
Symposium 2013

22.11.13
Limitations and deficiencies
Impossible to evaluate clinically.
Highly inefficient 1 in 2 embryos implant.
World fertility rates decline.
Assisted conception techniques require more research to increase effectiveness.

What we know
Endometrial
receptivity
- Molecular characteristics acquired by the endometrial cells for interaction with the embryonic trophoblasts
- Adhesion molecules:
Integrins
Selectins
Glycans
Keratan sulfate
Sialyl Lexis X

- Extracellular Matrix

- Microvillous surface
- Chemokines:
CXCL1
CCL7

- Cytokines:
IL-1B
IL-1ra
MCP-1
IFN-y

Can endometrial receptivity be affected?
Sterile inflammation:
Tissue remodeling
ECM fragments
Cell debris
Can the endometrium react to this stimuli?
Intracellular
pathogens
PAMPs
Extracellular
pathogens
Adapted from Nat Immunol, 2010 vol. 11 (5) pp. 373-84

The Toll-like Receptor Family sense pathogens

DAMPs
Can the uterus express these TLRs?
Expression of the TLRs in the uterus
Influenced by hormonal status
Endometrial TLR activation decreases trophoblast adhesion in vitro

Highest expression at the late secretory phase
Can endometrial TLR activation affect embryo implantation?
Endometrial cell line RL95-2
Choriocarcinoma - JAr cells
Choriocarcinoma spheroids - JAr Cells
In vitro implantation model
Endometrial TLR 5 activation decreases trophoblast spheroid adhesion
Aflatoonian, et al; Hum Reprod; 2007
Aboussahoud W., et al, Hum Reprod, 2010

TLR 2, 2/6 - Gram+
TLR 3 - Virus
TLR 9 - Intracellular bacteria
Big Question
?

How does endometrial TLR activation affects the intercellular adhesion?
Visualisation of endometrial cell microscopical structures
AFM
Allows to obtain 3D topography images of the cells
Mucosal immune responses
Mucin - Highly glycosilated membrane proteins:
Physical barrier.
Produced in gut and lungs during infections.

Present in the endometrium previous to implantation.
Absent in the implantation site.
TLR Signalling pathways
In vivo embryo implantation murine model
Verify the biological effect in vivo.
TLR activation induced
microstructural changes
TLR 2/6 and TLR 3 Stimulation
Loss of microvilli and membrane blebbing
Time lapse measurements
Waviness (um)
Roughness (nm)
Detrimental effect in tissue architecture
Effects in embryo implantation
Reduced implantation
Increased resorption
FSL-1 treatment increased:
IL-1B
IL-1RA
MCP-1
Key cytokines for
implantation
Simulated infection. Flagellin - TLR 5
Mucin 1
Mucin 16
A) Assessment the role of TLR 5 activation during the embryo implantation process. (Already performed)

FSL-1 (TLR6)
10 Blastocysts
Left UH
Aknowledgments:

AURDM

Alireza Fazeli
Sarah Elliott
Mehrnaz Montazeri
Nasim Maslehat
Shaghayegh Basatvat
Ignacio Caballero
INIA

Alfonso Gutiérrez-Adán
Alexandra Calle
Raúl Fernández González
Full transcript