Rat resident testicular macrophages have an alternatively activated phenotype and constitutively produce interleukin-10 in vitro

Abstract

The ability of the rodent testis to tolerate graft alloantigens and spermatogenic cell autoantigens is well known. The mechanisms underlying this "immune privilege" are poorly understood, but the numerous resident TMs have been implicated. Although it has been assumed that TMs display a phenotype consistent with immune privilege, this has not been formally established. Consequently, TMs were isolated from adult rats and cultured under basal conditions and following stimulation with LPS and IFN-γ (classical activation) or IL-4 (alternative activation). BMMs matured in vitro were used as control. Expression of the classical (proinflammatory) activation markers TNF-α, IL-1β, iNOS, IL-6, RANTES, IL-12p40, and SOCS3 and alternative (immunoregulatory) activation markers IL-10, TGF-β1, CXCL2, and SOCS1 was measured by QPCR or ELISA. In culture, TMs were characterized by poor expression of classical activation genes and TGF-β1 but constitutively high IL-10 production and reduced costimulatory activity in a polyclonal T cell activation assay. This pattern of gene expression was associated with TMs expressing the scavenger receptor CD163, which is characteristic of tissue resident macrophages and alternative activation. By contrast, CD163-negative TMs displayed reduced inflammatory gene expression but did not constitutively produce IL-10. These data indicate that under the influence of the testicular environment, macrophages adopt an alternatively activated phenotype, involving reduced capacity for proinflammatory gene expression, constitutive IL-10 production, and impaired ability to support T cell activation, consistent with a role in maintaining testicular immune privilege.

Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

“…of SeC in NOD mice partially reversed the pathology with the recovery of β cell function thanks to restoration of the systemic immune tolerance through a TGF-β/IDO-dependent mechanism that led to emergence of regulatory T cells (Tregs) [94]. Moreover, it has been demonstrated that TGF-β with IL-10 and activin-A, released by SeC, contribute to modulate the immune cell response in the testis, stimulating immune cells involved in the tolerogenic response, such as M2 (anti-inflammatory) macrophages, and Th2 and Treg cells [95]. Accordingly, most macrophages located in the testis show an M2 phenotype [96].…”

Testicular defense systems: immune privilege and innate immunity

“…37 Moreover, testicular macrophages in rats are less activated in response to pathogen stimulation, and they constitutively produce anti-inflammatory cytokines. 38,39 These phenotypes support testicular immune privilege. By contrast, circulating macrophages significantly infiltrate the testis in orchitis and are detrimental to spermatogenesis.…”

Differential Activation of Inflammatory Pathways in Testicular Macrophages Provides a Rationale for Their Subdued Inflammatory Capacity

“…12,13). Recently, Winnall et al (14) reported that the immune response of TM is skewed toward an alternatively activated macrophage type similar to the M2 type in mice upon treatment with both classical (LPS and IFN-g) or alternative (IL-4) activation ligands, although still a reduced capacity for proinflammatory gene expression was observed. In support of these observations, incubation with uropathogenic Escherichia coli instead of LPS increased mRNA expression of the proinflammatory cytokines IL-6 and TNF-a; however, protein levels were not elevated (15).…”