Renal Macrophage Biology

PROJECT SUMMARY/ABSTRACT Renal macrophages (RMs) are myeloid cells residing in renal tissue that fulfill specific renal functions including homeostasis, immune surveillance, and repair. RMs account for about 50% of total CD45+ leukocytes in mouse kidneys and are also found in large numbers in the human kidney. They consist of embryo-derived (EMRMs) and bone marrow (BM)-derived RMs (BMRMs). Recently, Ide, et al. found that yolk-sac-derived renal macrophages (YSRMs)[5] contribute a very small portion of RMs at birth, but progressively expand in number with age and become a major contributor to the RM population in older mice. The macrophages’ niche in tissues such as brain, liver, and lung may determine the specific functions of the tissue macrophages (TMs). Only a small number of the niche signals have been described for these TMs, and the specific molecular mechanism underlying RM regeneration has not been studied. Understanding the mechanisms of the RM niches will be critical to the development of therapeutics for kidney diseases that block or induce specific signaling pathways. How RM niches impact RM longevity, fate, dynamics, and immune metabolic responses remains unclear. To address these questions, we have applied a recently generated Cre induced-human CD59 transgenic line (ihCD59) to trace RM lineage and determine the intrinsic properties of RMs of BM or embryonic origins. We find that RMs are mainly derived from fetal liver monocytes before birth, but self-maintain through adulthood with contributions from peripheral monocytes. At a steady state, deficiency of CX3CR1, but not of CCR2, significantly reduces the number of RMs, but not microglia, from birth through adulthood. Our preliminary results suggest the CX3CR1/CX3CL1 axis is indispensable for specific regeneration and maintenance of RMs. Although the role of CX3CR1/CX3CL1 in the progression of various diseases in tissues (including kidney tissue) has been recognized for many years, its critical role in this niche signaling for RMs of BM, embryonic, and yolk-sac origins has not been studied. Fractalkine/CX3CL1 exists as a membrane- anchored molecule as well as in soluble form, each mediating different biological activities. However, the roles for these two types of CX3CL1 in RM regeneration and maintenance remain unknown. Therefore, we propose to examine our working hypothesis that the CX3CL1 signaling pathway is critical for CX3CR1+RM longevity, fate, dynamics, and immune metabolic responses under normal (Aim 1) and pathological conditions (Aim 2). In Aim 3, we will examine the cellular and molecular mechanisms by which the CX3CR1/CX3CL1 axis contributes specifically to RM regeneration and maintenance. Successful completion of these Aims will advance our understanding of tissue macrophage biology, and specifically of RMs which will allow for improved design and development of therapeutics for kidney disease that block or induce specific signaling pathways.