Two populations of self-maintaining monocyte-independent macrophages exist in adult epididymis and testis

Abstract

Macrophages are the principal immune cells of the epididymis and testis, but their origins, heterogeneity, development, and maintenance are not well understood. Here, we describe distinct populations of epididymal and testicular macrophages that display an organ-specific cellular identity. Combining in vivo fate-mapping, chimeric and parabiotic mouse models with in-depth cellular analyses, we found that CD64hiMHCIIlo and CD64loMHCIIhi macrophage populations of epididymis and testis arise sequentially from yolk sac erythro-myeloid progenitors, embryonic hematopoiesis, and nascent neonatal monocytes. While monocytes were the major developmental source of both epididymal and testicular macrophages, both populations self-maintain in the steady-state independent of bone marrow hematopoietic precursors. However, after radiation-induced macrophage ablation or during infection, bone marrow-derived circulating monocytes are recruited to the epididymis and testis, giving rise to inflammatory macrophages that promote tissue damage. These results define the layered ontogeny, maintenance and inflammatory response of macrophage populations in the male reproductive organs.

Impacts of Immunometabolism on Male Reproduction

“…According to the morphology and localization, human testicular macrophages could be classified into interstitial and peritubular macrophages; but no marker has been found to distinguish both types ( 86 ). Unlike in humans, mouse testicular interstitial and peritubular macrophages were characterized by CD64 hi MHCII lo and CD64 lo MHCII hi , respectively ( 87 , 88 ). Once established in the niche, except the empty niche, these macrophages self-maintain for long periods of time without replenishment from blood monocytes in the steady condition ( 88 ).…”

“…Unlike in humans, mouse testicular interstitial and peritubular macrophages were characterized by CD64 hi MHCII lo and CD64 lo MHCII hi , respectively ( 87 , 88 ). Once established in the niche, except the empty niche, these macrophages self-maintain for long periods of time without replenishment from blood monocytes in the steady condition ( 88 ). Interstitial macrophages closely contact with Leydig cells, which might contribute to facilitate testosterone.…”

“…In fact, rat testicular macrophages characterized by high level of CD163 that were related to maintain testicular immune privilege through secreting large amounts of the anti-inflammatory cytokine like IL-10, and inducing expansion of immunosuppressive Tregs ( 81 , 85 , 99 ). Similarly, macrophages in mouse testes also display an immunosuppressive phenotype by expressing significantly higher levels of immunosuppressive genes, namely Mrc1 , Dab2 , Igf1 , and Lgals3 ( 88 ). In accordance with these evidences, previous data suggested that the number of CD25 + Foxp3 + Tregs would increase after coculture of testicular macrophages and splenic T cells ( 81 ).…”

Exploring the Ion Channel TRPV2 and Testicular Macrophages in Mouse Testis

“…Hence, the hormonal imbalances in the testes of these mice likely had initiated changes in the macrophage populations, resulting in the acquisition of this unique population. Whether the changes involve recruitment of a new macrophage population, as recently suggested to occur after radiation or infection [ 19 ] and whether or to which degree the factors of the local environment contribute to these changes [ 15 ], remain to be investigated.…”

“…Already at birth, a testicular compartment, i.e., the interstitial space is occupied by CD206 + MHC II - macrophages, whereas CD206 - MHC II + ones surround the seminiferous tubules. Furthermore, a new study showed that after radiation or during infection, bone marrow-derived circulating monocytes are recruited to the testis and give rise to inflammatory macrophages which then promote tissue damage [ 19 ]. Hence, testicular macrophages can be heterogeneous.…”