Phenotypic and functional heterogeneity of the testicular macrophage population: a new regulatory model

Testicular macrophages (TMs) are important contributors to the response of the testis to infection, as well as the regulation of spermatogenesis, steroidogenesis and other homeostatic functions of the testis. The TMs are the largest population of immune cells in a region of tight immunoregulation, where both innate and acquired immune responses are effectively suppressed, and these cells are predicted to be responsible for regulating this immunosuppression. In the rat, TMs have been broadly classified into two main populations, designated "newly arrived" and "resident", the latter being characterised by expression of the scavenger receptor, CD163. Systemic inflammation in response to lipopolysaccharide leads to an influx of CD163(-) monocyte-like ("infiltrating") macrophages into the rodent testis, which have a pro-inflammatory phenotype and express interleukin-1β, tumour necrosis factor-α, inducible nitric oxide synthase and other inflammatory factors. The resident CD163(+) TMs, on the other hand, constitutively produce IL-10 and are poor stimulators of T-cell proliferation in vitro, indicating that they contribute to testicular immunosuppression. However, our recent studies have demonstrated that the "newly-arrived" CD163(-) TMs present in the rat testis under normal homeostatic conditions show very little response to LPS stimulation in vitro. We here propose a modified model of TM heterogeneity whereby the CD163(-) TMs of the normal rat testis are derived from a monocyte subset that continuously repopulates the testis, and is distinct from the monocyte-like "infiltrating" subset from which pro-inflammatory CD163(-) TMs may be derived during systemic inflammation.