Characterization of the Micro-Environment of the Testis that Shapes the Phenotype and Function of Testicular Macrophages

Abstract

Macrophages are important in the activation of innate immune responses and in a tissue-specific manner in the maintenance of organ homeostasis. Testicular macrophages (TM), which reside in the testicular interstitial space, comprise the largest leukocyte population in the testes and are assumed to play a relevant function in maintaining testicular immune privilege. Numerous studies have indicated that the interstitial fluid (IF) surrounding the TM has immunosuppressive properties, which may influence the phenotype of TM. However, the identity of the immunosuppressive molecules present in the IF is poorly characterized. We show that the rat testicular IF shifted GM-CSF–induced M1 toward the M2 macrophage phenotype. IF-polarized M2 macrophages mimic the properties of TM, such as increased expression of CD163, high secretion of IL-10, and low secretion of TNF-α. In addition, IF-polarized macrophages display immunoregulatory functions by inducing expansion of immunosuppressive regulatory T cells. We further found that corticosterone was the principal immunosuppressive molecule present in the IF and that the glucocorticoid receptor is needed for induction of the testis-specific phenotype of TM. In addition, TM locally produce small amounts of corticosterone, which suppresses the basal expression of inflammatory genes as a means to render TM refractory to inflammatory stimuli. Taken together, these results suggest that the corticosterone present in the testicular environment shapes the immunosuppressive function and phenotype of TM and that this steroid may play an important role in the establishment and sustenance of the immune privilege of the testis.

Microenvironmental signals govern the cellular identity of testicular macrophages

“…However, recent data from rats, using flow cytometry, suggest that all TM are positive for CD68 (CD163 + CD68 + [≈75%] and CD163 − CD68 + [25%]). This is in contrast to previous studies, where only ≈57% of TM were found to be positive for CD68 . The expression of the costimulatory molecules CD80 and CD86 was completely absent in rat TM, with about half of the TM positive for MHC class II, again determined by flow cytometry .…”

“…However, the complete absence of CD80 and CD86 expression in TM, together with partial expression of MHC II (≈ 50% of TM), suggests that TM have an impaired ability to present Ags to T and B cells, and thus have a limited capacity to activate adaptive immunity. In support of this idea, TM were shown to have a reduced costimulatory function on T cells, while inducing the expansion of splenic T cells to immunosuppressive Tregs . The reduced presentation of Ags to T cells could possibly be a means to protect from autoimmune attack against autoantigens on developing germ cells, and thus a mechanism to maintain testicular immune privilege.…”

“…Although peritubular and interstitial TM differ in their regulation of archetypical testicular functions (spermatogenesis and steroidogenesis, respectively), both possibly contribute to the establishment of testicular immune privilege, by displaying an immunoregulatory M2 macrophage phenotype . In this regard, TM are characterized by the expression of a low number of proinflammatory genes, with concomitant high expression levels of a large number of M2 macrophage phenotype genes, such as CD163 …”

“…Accumulating evidence clearly points to a central role of TM in the maintenance of testicular immune privilege . Here, the major role of TM seems to be their fine‐tuned response to inflammatory cues, to which they react with a subdued anti‐inflammatory response, thus protecting the delicate germ cells from a "cytokine storm."…”

Hair growth control by innate immunocytes: Perifollicular macrophages revisited

“…As a key component of the mononuclear phagocyte network, these innate immune cells present antigens to cells of the adaptive immune system . Additionally, MACs entrench themselves in the physiology of their host tissues, where they live extended life spans and respond to changes in the environment with alterations in their own functional state to maintain local homeostasis …”