Abstract: Certain populations of tissue-resident macrophages are maintained by self-renewal and longevity while others are continually replenished from circulating monocytes, yet the basis for these tissue-specific differences and the downstream effect on macrophage function is unclear. Furthermore, inflammation generally leads to recruitment of abundant monocyte-derived macrophages, but what regulates the fate of these cells and the extent to which they can assume the identity and function of resident macrophages also remains unclear. To address these questions, we have studied the factors governing the behaviour of peritoneal macrophages. We have found that under non-inflamed conditions, replenishment of peritoneal macrophages from the bone marrow occurs in a sexually dimorphic manner and that this leads to sex-differences in macrophage phenotype and ability to protect against peritonitis. These data establish that the rate-of-replenishment from the bone marrow plays a key role in the function of tissue-resident macrophages and highlights the importance of considering both sex and age in susceptibility to inflammatory and infectious diseases. Following inflammation, we found that recruited monocyte-derived inflammatory macrophages persist long-term but in an immature transitory state of differentiation that is characterised by defective responsiveness to secondary immune challenge. Critically, rather than being pre-programmed this immature state was a direct consequence of the presence of enduring established resident macrophages. Hence, competitive pressure between incoming monocytes and established tissue resident macrophages may an underlying driving force for the evolution of tissue-resident macrophage autonomy. These data have major implications for understanding the long-term effects of inflammation on tissue health and responsiveness to future disease.

Biography: Steve Jenkins is a Lecturer at the University of Edinburgh’s Centre for Inflammation Research. He obtained his PhD in Parasite Immunology at the University of York before undertaking post-doctoral research with Profs Andrew MacDonald and Judith Allen at the University of Edinburgh on the regulation of adaptive and innate immune responses during helminth infection. During this time he discovered of an alternative process of inflammation whereby macrophages increase in number independently of monocyte recruitment through rapid proliferation of tissue resident cells (Science, 2011, PMC3128495; J Ex Med, 2013, PMC3804948), which helped stem a major re-assessment of the ontogeny of macrophages during homeostasis and disease. He subsequently moved the University of Edinburgh’s Centre for Inflammation Research to establish his own research group focusing on how macrophage survival, proliferation and function is regulated during inflammatory disease, and received tenure in 2016. His recent work has included defining the effect of cell origin, time-in-tissues, inflammation exposure, and biological sex on the function and proliferative capacity of tissue macrophages, and how this effects resistance to bacterial infection.

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