Role of galectin 3 in the inflammatory response and fibrotic remodelling during chronic epididymo-orchitis

• Applicant: Dr. Monika Fijak
• Subject Area: Reproductive Medicine, Urology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 513975149

Infection and inflammation of the male reproductive tract are one of the most important aetiologies of male infertility. In asymptomatic patients, inflammatory reactions in the testis are diagnosed only by invasive biopsy. Since deeper insight into testicular and epididymal immunopathologies and their contribution to infertility is needed, a limited access to human samples can be overcome by using animal models. Experimental autoimmune epididymo-orchitis (EAEO) is a well established rodent model of autoimmune-based inflammation mimicking pathology observed in the human testis and epididymis that can lead to infertility. The invading immune cells secrete pro-inflammatory mediators and support tissue remodeling. Subsequent disruption of spermatogenesis, thickening of the lamina propria and fibrosis contribute to loss of the adluminal compartment and subsequent aspermatogenesis. In the EAEO the population of testicular macrophages (TMφ) is strongly increased and express pro-inflammatory mediators. Mφ are known to play an important role in tissue repair and are found in fibrotic stroma, however their exact role in fibrotic remodeling is still unknown. Galectins are the main components and players of the complex cellular glycocalyx. Galectin 3 (Gal-3) interacts with a variety of cell types involved in wound healing, induces migration of monocytes and increases the ratio of alternatively activated Mφ, which are involved in tissue repair and fibrotic remodeling. Our preliminary data show that TMφ express Gal-3 mainly during EAEO, pointing to the presence of Gal-3 in newly arriving Mφ. Altogether, our recent studies point to an important role of Gal-3 in regulation of spermatogenesis, steroidogenesis and maintenance of the TMφ population. Therefore, it is hypothesized that under normal conditions Gal-3 expressed by testicular somatic cells such as Sertoli cells (SC) contributes to normal spermatogenesis and testicular function. Upregulation of Gal-3 expression during the course of EAEO leads to an inflammatory response, fibrosis and subsequent tissue destruction. General or cell specific ablation of Gal-3 in SC or in Mφ contribute to inhibition of inflammatory and fibrotic responses in EAEO testes and epididymides. Therefore, in the proposed project following objectives will be investigated: (I) determination of influence of SC-derived Gal-3 on spermatogenesis, steroidogenesis and maintenance of TMφ by using conditional Lgals3 depletion in SC (Lgals3-/-SC); (II) analysis of Gal-3 function during inflammatory and fibrotic responses in the testis and epididymis by using constitutive Gal-3 (Lgals3-/-) KO mice. Furthermore, (III) it will be elucidated how a cell specific-depletion Gal-3 in SC or TMφ affects testicular immune response and development of fibrosis. Understanding, how Gal-3 influences spermatogenesis and testicular/ epididymal immune response will help to delineate mechanisms leading to fibrotic remodelling in these organs.

• DFG Programme: Research Grants