a relationship between inflammatory cytokine receptors and

A relationship between inflammatory cytokine receptors and ion channel expression in endometriotic lesions

Universitätsklinik für Frauenheilkunde [email protected]

2

Universitätsklinik für Frauenheilkunde

Endometriotic-associated nerve fibers

A B

C D

E F

McKinnon B, Bersinger NA, Wotzkow C, Mueller MD. Endometriosis-associated nerve fibers, peritoneal fluid cytokine concentrations, and pain in endometriotic lesions from different locations. Fertil Steril. 2012 Feb;97(2):373–80.

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Cytokine concentrations and endometriosis associated nerve

McKinnon B, Bersinger NA, Wotzkow C, Mueller MD. Endometriosis-associated nerve fibers, peritoneal fluid cytokine concentrations, and pain in endometriotic lesions from different locations. Fertil Steril. 2012 Feb;97(2):373–80.

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Inflammation and nerve fiber interaction in endometriotic pain;

McKinnon BD, Bertschi D, Bersinger NA, Mueller MD. Inflammation and nerve fiber interaction in endometriotic pain. Trends Endocrinol Metab. 2015 Jan;26(1):1–10.

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Study aim;

-Determine the expression of cytokine receptors and ion channels in endometriotic tissue, the relationship between them and their cellular localisation;

6


No Endo Endo Peritoneal Ovarian RVS

0.03

1.00

32.00

rela

tive

mR

NA

exp

ress

ion

TNFR1

Eutopic Ectopic

*** ***

Cytokine receptors and ion channel mRNA expression in endometrial and endometriosis tissue;

Cytokine Receptors

Purinergic Receptors Voltage gated sodium channel


0.03

1.00

32.00

rela

tive

mR

NA

exp

ress

ion

CCR5

*** *** *

Eutopic Ectopic


0.03

1.00

32.00

rela

tive

mR

NA

exp

ress

ion

SCN9A

** ***

Eutopic EctopicNo Endo Endo Peritoneal Ovarian RVS0.03

1.00

32.00

1024.00

rela

tive

mR

NA

exp

ress

ion

P2X3

Eutopic Ectopic


0.03

1.00

32.00

rela

tive

mR

NA

exp

ress

ion

P2X4

Eutopic Ectopic

*** ***

Endo Non-Endo

Eutopic Ectopic

P O RVS

E NE

Eutopic Ectopic

P O RVS No Endo Endo Peritoneal Ovarian RVS

0.03

1.00

32.00

rela

tive

mRN

A e

xpre

ssio

nSCN3A

*** ***

Eutopic EctopicE NE

Eutopic Ectopic

P O RVS E NE

Eutopic Ectopic

P O RVS E NE

Eutopic Ectopic

P O RVS

Endo Non-Endo

Eutopic Ectopic

P O RVS

P2X3 P2X4

CCR5 TNFR1

SCN3A SCN9A

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Relationship between cytokine receptors and ion channels in ectopic lesions;

Correlation; CCR5 v Purinergic Receptors Correlation; CCR5 v Voltage gated sodium channel SCN9A

0 1 2 3 4 50.00

5.00

10.00

15.00Linear reg. of CCR5:Line

1 2 3 4 5-5.00

0.00

5.00

10.00

15.00

CCR5

SCN

3A

SCN3AP2X3

0.25 0.5 1 2 4 80.03

1.00

32.00

1024.00

CCR5

P2X

3

P2X4

0 1 2 3 4 50.00

2.00

4.00

6.00

8.00

CCR5

P2X4

Correlation; TNFR1 v Purinergic Receptors Correlation; TNFR1 v Voltage gated sodium channel

P2X3

1 2 4 80.03

1.00

32.00

1024.00

P2X3

TNFR1

P2X4

1 2 4 81.00

2.00

4.00

8.00P2X4

TNFR1

SCN3A

1 2 4 80.50

1.00

2.00

4.00

8.00

16.00

SCN3A

TNFR1

SCN9A

1 2 4 80.120.250.501.002.004.008.0016.00

TNFR1

SCN9A

n = 21, r = 0.036, p = 0.876

n = 21, r = -0.294, p = 0.1958

n = 21, r = 0.546, p = 0.0104

n = 21, r = 0.265, p = 0.245

n = 21, r = -0.145, p = 0.531

n = 21, r = 0.297, p = 0.192

n = 21, r = -0.059, p = 0.799

n = 21, r = -0.13, p = 0.554

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CCR5 and SCN3A expression in endometriotic associated nerves;

CCR5 +ve CCR5 -ve0

2000

4000

6000

8000

SC

N3A

exp

ress

ion

(Flu

ores

cene

inte

nsity

)

**

Overlay CCR5 SCN3A (Nav1.3)

Nerve cells positive for CCR5 have significantly stronger SCN3A expression

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Increased Nav1.3 expression in CCR positive endometriosis-associated nerves

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Conclusions

• CCR5, TNFR1, P2X4, SCN3A and SCN9A are increased in ectopic endometriosis

• CCR5 and SCN3A expression are related and co-localised

• Positive CCR5 expression results in increased SCN3A expression

RANTES- through interaction with CCR5 receptor may stimulate an increase in SCN3A expression – possible mechanism in increased pain transmission

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Acknowledgements

Endometriosis and Gynaecological Oncology Laboratory •  Prof Nick Bersinger •  Dr Vida Kocbek •  Anne Vaucher

Department of Gynaecology, Frauenklinik, Bern

•  Prof Michael Müller •  Dr Kostantinos Nirgianakis •  Dr Sara Imboden

Live cell imaging Laboratory •  Dr Fabian Blank •  Carlos Wotzkow

a relationship between inflammatory cytokine receptors and

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