Origin of testicular macrophages and implication of testicular local microenvironment in metabolically shaping the immunosuppressive phenotype.

• Applicant: Dr. Sudhanshu Bhushan
• Subject Area: Reproductive Medicine, Urology ; Immunology
• Term: from 2013 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 245043199

Tissue-resident macrophages are the first line of defense against invading pathogens. Besides their immunological role, they are also required for the maintenance of the normal function of the organs to maintain homeostasis. Most tissue-resident macrophages are derived from embryonic precursors (yolk sac (YS), macrophage/fetal liver monocytes (FL-MOs)) and bone marrow monocytes (BM-MOs). Upon organ entry, tissue-specific signals govern the functional polarization of macrophages to perform tissue-specific functions. Testicular macrophages (TM) comprise the largest immune cell population of the testis and reside in the testicular interstitial space. Our preparatory work clearly showed that BM-MOs contribute only minimally to the pool of the adult TM population. Moreover, TM display an M2 macrophage phenotype to maintain the immune privileged status of the testis. The immunosuppressive phenotype and function of TM are established and sustained by the testicular microenvironment, namely the testicular interstitial fluid (IF). Although our data obtained in the previous funding round suggest that the testicular microenvironment shapes the phenotype and function of TM, it is unclear to date what molecular changes are implemented by this in TM. In addition, our data suggest that TM display an M2 macrophage phenotype even after treatment with inflammatory stimuli which is indicative for a role of cellular metabolites in functional polarization of TM to an M2 macrophage phenotype.Based on these observations, we hypothesize that TM originate from embryonic progenitors in the yolk sac (YS) and/or fetal liver (FL), migrate and colonize the testicular microenvironment, where they polarize to an M2 macrophage phenotype by altering their metabolic profile, thus maintaining the immunosuppressive environment of the testis. Hence, in this proposed study, we aim to investigate whether (i) adult TM are derived from YS and/or FL embryonic progenitors, (ii) progenitor cells of macrophages or alternatively the testicular niche govern the phenotype of TM, (iii) the functional role of TM in normal testicular function and in response to tissue injury/inflammation, and finally (iv) the metabolic profile of TM plays a role in maintaining the M2 phenotype.

• DFG Programme: Research Grants