Macrophage-Specific Toll Like Receptor 9 (TLR9) Causes Corpus Cavernosum
Dysfunction in Mice Fed a High Fat Diet.
Authors Priviero F, Calmasini F, Dela Justina V, Wenceslau CF, McCarthy CG, Webb RC
Submitted By Clinton Webb on 5/5/2021
Status Published
Journal The journal of sexual medicine
Year 2021
Date Published
Volume : Pages 18 : 723 - 731
PubMed Reference 33741290
Abstract Erectile dysfunction (ED) has been shown to be related with inflammatory markers
in humans. Chronic infusion of TNF-a caused ED in mice while TNF-a knockout mice
exhibited improvement in the relaxation of the corpus cavernosum (CC)., Since
obesity triggers an inflammatory process, we aimed to investigate the hypothesis
that in obesity, Toll-like receptor 9 (TLR9) activation leads to increased TNF-a
levels and impairment in CC reactivity., Four-week old male C57BL6 (WT) and TLR9
mutant (TLR9MUT) mice were fed a standard chow or high fat diet (HFD) for 12
weeks. Body weight and nonfasting blood glucose were analyzed. Contractile and
relaxation responses of the CC were evaluated by electrical field stimulation
and concentration response curves to phenylephrine and acetylcholine. Protein
expression of nNOS, TNF-a, TNF-R1, TLR9 and MyD88 were measured by western blot.
Plasma levels of TNF-a were measured by ELISA., In obesity, impaired cavernosal
relaxation is associated with the activation of the innate immune system, by
increasing the production of TNF-a through the activation of TLR9 in the
macrophages., After 12 weeks of HFD both WT and TLR9MUT mice had increased body
weight and nonfasting blood glucose compared to standard chow. In the CC,
acetylcholine-induced relaxation was not changed. A trend to increased
contraction to phenylephrine and KCl was seen in WT HFD only. electrical field
stimulation-induced relaxation of the CC was decreased in WT HFD as well as nNOS
expression in the CC of WT HFD, but not in TLR9MUT HFD. In the CC, protein
expression of TLR9 and MyD88 was similar in all groups. While circulating levels
of TNF-a presented only a trend to increase in mice fed HFD, the CC expression
of TNF-a was increased only in WT HFD mice., The innate immune system can be a
target for the treatment of erectile complications in obesity., This is the
first study demonstrating that activation of TLR9 expressed in macrophages leads
to impaired cavernosal relaxation. The main limitation of the study is the lack
of understanding about the source/expression of the macrophages in the cavernous
tissue. Further, herein, the experiments were performed only in isolated
cavernous tissue (in vitro), thus the lack of knowledge on how the TLR9
modulates the in vivo response of the erectile tissue is another limitation of
this study., Our findings indicate that CC dysfunction observed in obesity is at
least in part mediated by the production of TNF-a upon activation of TLR9
expressed in the macrophages. Priviero F, Calmasini F, Dela Justina V, et al.
Macrophage-Specific Toll Like Receptor 9 (TLR9) Causes Corpus Cavernosum
Dysfunction in Mice Fed a High Fat Diet. J Sex Med 2021;18:723-731.

Investigators with authorship
Clinton WebbAugusta University