Targeting Monocyte Derived CCL17 Attenuates Murine Crescentic Glomerulonephritis by Affecting Renal CCR4<sup>+</sup> Regulatory T-Cell Recruitment

<b><i>Introduction:</i></b> The chemokine receptor CCR4 is expressed by diverse CD4⁺ T cell subsets including regulatory T cells (Tregs) but its functional importance for leukocyte recruitment and the relevance of its two corresponding chemokines CCL17 and CCL22 have not been studied in immune-mediated crescentic glomerulonephritis (cGN). <b><i>Methods:</i></b> Utilizing the single-cell RNA sequencing (scRNAseq) data in analyzing leukocytes isolated from both human and murine nephritic kidneys, we identified CCL17 as a potential therapeutic target in immune-mediated renal disease. Using a mouse model of murine cGN, we then delineated the effects of targeting CCL17 by neutralizing antibodies and in <i>Ccl17</i> gene-deficient mice. <b><i>Results:</i></b> Unsupervised scRNAseq analyses identified the CCL17-CCR4 axis as a mechanism potentially involved in renal T-cell migration. Analyses of functional kidney impairment and histopathological kidney damage revealed an attenuation of crescentic GN in anti-CCL17 antibody-treated mice which was corroborated using in <i>Ccl17</i> gene-deficient mice. Immunohistochemical analyses revealed that these changes were accompanied by an affected renal Treg recruitment in both experimental approaches. <b><i>Conclusion:</i></b> The chemokine receptor CCR4 and its corresponding chemokine CCL17 are expressed in human and murine cGN and targeting the CCR4-CCL17 axis by neutralizing antibodies as well as <i>Ccl17</i> gene deficiency led to increased renal Treg recruitment and reduced histological and functional kidney damage in murine cGN.