Neutrophil Gelatinase-Associated Lipocalin From Macrophages Plays a Critical Role in Renal Fibrosis Via the CCL5 (Chemokine Ligand 5)-Th2 Cells-IL4 (Interleukin 4) Pathway

Abstract

NGAL (neutrophil gelatinase-associated lipocalin; or lipocalin 2, Lcn2) is a novel mineralocorticoid target in the cardiovascular system. We showed that Lcn2 gene invalidation protects against proteinuria and renal injury upon mineralocorticoid excess and we hypothesized that NGAL produced from macrophages promotes the expression of chemoattractant molecules involved these renal lesions. The role of NGAL was analyzed using myeloid-specific (MΦ KO NGAL) Lcn2 knockout mice challenged with uni-nephrectomy, aldosterone, and salt (NAS) for 6 weeks. The role of the CCL5 (chemokine ligand 5) and IL4 (interleukin 4) in kidney fibrosis was studied by administration of the CCL5 receptor antagonist maraviroc or by injections of an anti-IL4 neutralizing antibody. In CTL mice, NAS increased the renal expression of extracellular matrix proteins, such as collagen I, αSMA, and fibronectin associated with interstitial fibrosis which were blunted in MΦ KO NGAL mice. The expression of CCL5 was blunted in sorted macrophages from MΦ KO NGAL mice challenged by NAS and in macrophages obtained from KO NGAL mice and challenged ex vivo with aldosterone and salt. The pharmacological blockade of the CCL5 receptor reduced renal fibrosis and the CD4 + Th cell infiltration induced by NAS. Neutralization of IL4 in NAS mice blunted kidney fibrosis and the overexpression of profibrotic proteins, such as collagen I, αSMA, and fibronectin. In conclusion, NGAL produced by macrophages plays a critical role in renal fibrosis and modulates the CCL5/IL4 pathway in mice exposed to mineralocorticoid excess.

MicroRNA-382 Promotes M2-Like Macrophage via the SIRP-α/STAT3 Signaling Pathway in Aristolochic Acid-Induced Renal Fibrosis

“…IL-1β and G-CSF were upregulated significantly in anti-miR-382+AA-CM, compared with anti-scramble+ AA-CM ( Figure 10K ). As reported in recent literature, CCL-5 and IL-4 were modulated by NGAL produced from macrophages and were proved to play a critical role in renal fibrosis ( 39 ). As our results show, CCL5 and IL-4 were elevated in AA-CM (Ctrl-CM as control) but were suppressed in anti-miR-382+AA-CM (anti-scramble+ AA-CM as control), suggesting that CCL-5 and IL-4 would be the critical mediators in the involvement of miR-382 on AA-induced CKD.…”

“…Interestingly, IL-4 and IL-13 are classical cytokines which have been proved to regulate macrophage M2 polarization ( 8 , 44 ). As reported in recent literature, CCL-5 and IL-4 were modulated by NGAL produced from macrophages and were proved to play a critical role in renal fibrosis ( 39 ). In breast cancer, IL-2 produced by myofibroblasts would promote post-radiation fibrosis ( 45 ).…”

Lipocalin-2: a novel link between the injured kidney and the bone

“…A new study shows that renal macrophages are actively producing LCN2 in AKI. Lcn2 deletion in macrophages decreased CCL5 production and partly blocked the CCL5/IL4 axis, leading to improved renal fibrosis, and low T-cell recruitment [109 ▪▪ ]. Renal macrophages produced LCN2 can also help manage iron trafficking in an optimal gradient, which contributes to tissue repair and recovery from AKI [108 ▪ ].…”

CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice

“…CCL5 has also been linked to excess ECM deposition (Passman et al ., 2021; Bonnard et al ., 2022). Brain ECM exists in diffuse and condensed forms and both types can restrict neuroplasticity (Miyata & Kitagawa, 2017).…”

“…In the present study, our aim was to explore the possibility that CCL5 and other potential ECM effectors that limit pyramidal arbor, gamma power and SWR abundance may be elevated in APOE4 human and TR mice. We also investigated the possibility that reductions in CCR5, a molecule linked to excess ECM deposition in other end organs as well as reduced plasticity in the brain (Passman et al ., 2021; Bonnard et al ., 2022; Shen et al ., 2022), might rescue biochemical, neurophysiological and/or behavioral alterations associated with this allele.…”