Cell-specific fluorescence-protein expression reveals clonal expansion in nephritis models
Mononuclear phagocytes (MNP) defend the kidney against infections, but may also promote the progression of sterile inflammation. Contrary to the previous concepts, these immune cells are not only recruited to the site of inflammation, but also expand from kidney-resident MNP. This could now be shown by ImmunoSensation2 member Prof. Christian Kurts and his team at the Institute of Molecular Medicine and Experimental Immunology at the University Hospital Bonn. The findings have recently been published in the journal Kidney International.
Mononuclear phagocytes (MNP), which include macrophages and dendritic cells, form a tissue-resident defense line against kidney-invading pathogens and contribute to the maintenance of renal homeostasis. In some cases, MNPs may also contribute to disease progression by driving local inflammation. Hence, MNP are known to be involved in the development of various kidney diseases, like crescentic glomerulonephritis and inflammasome-mediated tissue fibroses.
“Accumulation of MNPs is commonly observed in nephritis, and a reduction of MNPs was found to have a protective effect in most nephritis models”, says Prof. Christian Kurts, head of the Institute of Molecular Medicine and Experimental Immunology (IMMEI).
Accumulation of MNPs in renal diseases
The accumulation of MNPs in renal diseases is generally assumed to primarily result from the recruitment of circulating monocyte precursors. This recruitment is mediated by the local release of chemokines and cytokines. By blocking, for example, chemokines or the respective receptors, MNP migration can be successfully prohibited. “It has been shown, that blocking chemotaxis of MNPs ameliorates nephritis partially” states Junping Yin, lead author of the publication. “Hence, much research is focused on identifying the factors that attract monocytes and on treating nephritis by blocking them or their receptors.”
But what if blocking the recruitment of monocyte precursors does not completely prevent MNP accumulation? “Local proliferation of tissue-resident MNPs might be a second source” explains Prof. Kurts. “This would limit current therapeutic approaches to treat nephritis only by blocking MNP recruitment.” The disease models currently used to investigate MNP involvement in renal diseases do not allow distinguishing the origin of these cells.
Adapted “Confetti-Mouse” model reveals clonal expansion
The present study used an elegant multicolor-fluorescence reporter mouse that stochastically expresses different fluorochromes in MNPs. For identification, four fluorescent proteins were introduced, only one of which is irreversibly expressed per cell: Green fluorescent protein, yellow fluorescent protein, red fluorescent protein, and cyan fluorescent protein. Thus, MNP recruited to the kidney may have any of these four colors. Strikingly, the team of Prof. Kurts observed clusters that displayed only one of the fluorescence colors. “The presence of only one color clearly indicates that these MNPs were not recruited, but were generated by clonal expansion” Junping Yin explains. This finding implies that therapeutic attempts to solely inhibit monocyte accumulation may not be completely effective, as pathogenic cells expand also from tissue-resident cells. This mechanism needs to be considered during nephritis therapy development.
Junpin Yin, Qi Mei, (et. al.), Fate mapping reveals compartment-specific clonal expansion of mononuclear phagocytes during kidney disease, Kidney International, June 2023, DOI: https://doi.org/10.1016/j.kint.2023.04.031.
Insitute of Molecular Medicine and Experimental Immunology (IMMEI)
University Hospital Bonn
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