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Targeting pro-fibrotic macrophages with bioactive self-assembly peptides to retard kidney fibrosis – know thyself

Cellular & Molecular Immunology volume 21, pages 935–937 (2024)Cite this article

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Chronic Kidney Disease (CKD) represents a growing global health burden with up to 25% of adults 60 or over having CKD. This is a huge challenge and most disease is progressive and can lead to lifelong dialysis or renal transplant. Although the triggers of CKD can be multiple and diverse they all eventually lead to progressive fibrosis of the kidney with increased deposition of collagen and other extracellular matrix molecules with increased inflammation also. Antibodies targeting Transforming Growth Factor-β TGF-β, a highly pro-fibrotic cytokine, have yielded disappointing results. Because inflammation is considered important in the disease initiation and progression targeting this to mitigate disease could be important, however inflammation is also necessary for kidney repair. In this issue of Cellular and Molecular Immunology Ouyang et al. identify a key pro-fibrotic macrophage subset and construct a 12-mer peptide that specifically targets these cells and elicits macrophage cell death in vivo and showed excellent efficacy in an animal model of kidney disease [1]. The efficacy of this molecule suggests that this could have translational value in human CKD.

Whatever the initial insult or injury to the kidney the end stage of the disease is often associated with kidney fibrosis. Triggers of inflammation in the kidney lead to an influx of inflammatory cells and whilst inflammation is critical in the normal repair of the kidney, unresolved inflammation promotes further damage and CKD. After initial injury or insult one of the most prominent cell types recruited to the kidney is neutrophils [2], where they release ROS and cytokines and macrophages that can also secrete a variety of cytokines and direct adaptive immunity [3]. Studies have identified contradictory results of depletion of macrophages dependant on method used and heterogeneity of macrophages [3]. For example, diphtheria toxin removal of Cd11 cells did not reduce renal damage but clodronate removal of macrophages did [3] likely through selectivity of macrophage subpopulations. Here Ouyang identified a subpopulation of macrophages using an ischeamia-reperfusion kidney mouse model. Using single-cell RNA sequencing on CD45+ sorted immune cells from the kidney this identified multiple clusters of macrophage cells but one cluster that expressed CD206 (MRC1), SPP1, and Fn1. Flow cytometry and immunofluorescence in situ confirmed their abundance in the kidney tissue. CD206 is generally considered a marker of the so called M2 phenotype. In what is more likely a spectrum, macrophages are generally placed into an ‘M1’ or ‘M2’ phenotype where the M1 phenotype marked by CD86 and triggered by LPS/TLR4 and interferon-γ, and M2 marked by CD206 expression and induced by IL-4 and IL-13. M1 are considered pro-inflammatory and M2 are considered reparative and pro-fibrotic. Interestingly a macrophage population of SPP1+, Fn1+, and Arg1+ have been shown to be pro-fibrotic in heart fibrosis via secreting CXCL4 [4]. Further, a similar macrophage subtype has been found in heart fibrosis [5] demonstrating commonality across organs. SPP1 encodes for the protein osteopontin and this has also been demonstrated to be released from macrophages in systemic sclerosis-a systemic fibrotic disease [6].

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  1. Department of Biosciences, Durham University, South Road, Durham, UK

    Steven O’Reilly

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O’Reilly, S. Targeting pro-fibrotic macrophages with bioactive self-assembly peptides to retard kidney fibrosis – know thyself. Cell Mol Immunol 21, 935–937 (2024). https://doi.org/10.1038/s41423-024-01194-2

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