The life and times of macrophages: only the good die young?

Abstract: Tissue-resident macrophages can be maintained by self-renewal/longevity or replenishment from circulating monocytes, but the costs and benefits of these different strategies remains unclear. We have studied this question in the context of tissue maintenance, regulation of inflammation and inflammation resolution in the serous cavities. We have shown that under non-inflammatory conditions, peritoneal macrophages are replenished from the bone marrow in a sexually dimorphic manner and that this difference in origin contributes to sex-differences in macrophage phenotype and ability to protect against peritonitis.

These data establish that the mechanism of macrophage maintenance (self-renewal vs recruitment) plays a key role in the function of tissue-resident macrophages. Furthermore, we have found that monocyte-derived macrophages recruited during inflammation persist in the cavity long-term yet remain in a transitory state of differentiation characterised by defective responsiveness to secondary immune challenge. Rather than being preprogramed, this altered state appears to arise as a consequence of competition with enduring established resident macrophages. Hence, competition between incoming monocytes and established tissue resident macrophages leads to heterogeneity in function of peritoneal macrophages.

These data provide a rationale for the advantage of maintaining macrophages by self-renewal in certain tissues. The distinct behaviour and the functional relevance of these transitory recruited macrophages will be discussed.