Uropathogenic E. coli Induce Different Immune Response in Testicular and Peritoneal Macrophages: Implications for Testicular Immune Privilege

PLoS One

Gerhard Schuler¹  Florian Wagenlehner²  Adrian Pilatz²  Sudhanshu Bhushan³  Andreas Meinhardt³  Yongning Lu³  Zbigniew Mikulski³  Jörg Klug³  Hamid Hossain⁴  Andreas Geisler⁴  Svetlin Tchatalbachev⁴  Trinad Chakraborty⁴ 

[1] Clinic for Obstetrics, Gynecology and Andrology of Large and Small Animals, Justus-Liebig-University Giessen, Giessen, Germany;Clinic of Urology, Pediatric Urology and Andrology, Justus-Liebig-University Giessen, Giessen, Germany;Department of Anatomy and Cell Biology, Unit of Reproductive Biology, Justus-Liebig-University Giessen, Giessen, Germany;Department of Medical Microbiology, Justus-Liebig-University Giessen, Giessen, Germany

关键词: Cytokines;    Macrophages;    Immune response;    Gene regulation;    Gene expression;    Calcium signaling;    Secretion;    Testosterone;   

DOI  :  10.1371/journal.pone.0028452

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Infertility affects one in seven couples and ascending bacterial infections of the male genitourinary tract by Escherichia coli are an important cause of male factor infertility. Thus understanding mechanisms by which immunocompetent cells such as testicular macrophages (TM) respond to infection and how bacterial pathogens manipulate defense pathways is of importance. Whole genome expression profiling of TM and peritoneal macrophages (PM) infected with uropathogenic E. coli (UPEC) revealed major differences in regulated genes. However, a multitude of genes implicated in calcium signaling pathways was a common feature which indicated a role of calcium-dependent nuclear factor of activated T cells (NFAT) signaling. UPEC-dependent NFAT activation was confirmed in both cultured TM and in TM in an in vivo UPEC infectious rat orchitis model. Elevated expression of NFATC2-regulated anti-inflammatory cytokines was found in TM (IL-4, IL-13) and PM (IL-3, IL-4, IL-13). NFATC2 is activated by rapid influx of calcium, an activity delineated to the pore forming toxin alpha-hemolysin by bacterial mutant analysis. Alpha-hemolysin suppressed IL-6 and TNF-α cytokine release from PM and caused differential activation of MAP kinase and AP-1 signaling pathways in TM and PM leading to reciprocal expression of key pro-inflammatory cytokines in PM (IL-1α, IL-1β, IL-6 downregulated) and TM (IL-1β, IL-6 upregulated). In addition, unlike PM, LPS-treated TM were refractory to NFκB activation shown by the absence of degradation of IκBα and lack of pro-inflammatory cytokine secretion (IL-6, TNF-α). Taken together, these results suggest a mechanism to the conundrum by which TM initiate immune responses to bacteria, while maintaining testicular immune privilege with its ability to tolerate neo-autoantigens expressed on developing spermatogenic cells.

【 授权许可】

CC BY