Investigating the role of kidney mononuclear phagocytes in immune complex-induced inflammation.

Resident mononuclear phagocytes (MNPs) play key roles in tissue homeostasis, defence against infection and repair. Although MNPs have been studied for more than 130 years, there have been significant advances in our understanding of their role, origin, maintenance and interactions in recent years, due to advances in fate-mapping technologies and the ability to study cells at a single cell resolution. However, numerous studies carried out in different organs have highlighted the difficulty of drawing parallels between MNPs in different tissues, with tissue-specific variation in ontogeny, surface markers and function in MNPs from the gastrointestinal tract, the lungs or the brain. In the kidneys, myeloid cells have been associated with both aggravation and amelioration of a variety of diseases depending on the mouse strain and the model used but less is known about the subtypes of cells present within the tissue and their role in homeostasis. Using healthy and autoimmunity-prone mice, as well as single cell technologies, we characterized kidney MNP subsets at baseline and during autoimmune IgG immune complex (IC)-induced inflammation. We found that kidney MNPs could be divided into at least six subsets in healthy mice based on their expression of F4/80, CD11b and MHC II. These subsets differed in their localization within the organ, IgG Fc receptor expression, and their ability to survey the circulation and present MHC II-peptide complexes, the latter varying with IgG opsonization and IgG IC size. In autoimmune inflammation, one minor subset of F4/80hi CD11blow cells, referred to as MNP4s, expanded substantially. Single cell transcriptomics data confirmed previous descriptions that the F4/80hi subsets originated from the yolk-sac, while the other subsets arose from hematopoietic stem cells. Intravital, two-photon imaging showed that kidney MNPs constantly surveyed the interstitium with their dendrites and rapidly acquired circulating IgG IC. In the context of IC-induced inflammation, the transcriptome of the kidney MNP subsets changed, with an induction of Fc receptor signalling and type I interferon genes. In human kidneys, we similarly showed that several MNP subsets could be distinguished based on expression of CD14, HLA-DR, CD206, CD36 and CLEC5A. These cells avidly phagocytosed both free and IgG-opsonized antigens. Together this work substantially increases our understanding of the heterogeneity, ontogeny and function of kidney MNPs.Wellcome Trust/National Institutes of Health 4-year PhD studentshi