Abstract
Interleukin (IL)-17A signaling via Interleukin 17 receptor A (Il17ra) contributes to the inflammatory host response by inducing recruitment of innate immune cells, but also plays a role in homeostatic neutrophilic granulocyte regulation. Monocytes, the other main innate immune cell, have a longer life span and can pursue multiple differentiation pathways towards tissue macrophages. Monocytes are divided into two subpopulations by expression of the Ly6C/Gr1 surface marker in mice. We here investigated the role of Il17ra in monocyte homeostasis and macrophage generation. In Il17ra-/- and in mixed bone marrow chimeric wt/Il17ra-/- mice, the concentrations of circulating Il17ra-/-Gr1low monocytes were significantly decreased compared to wt cells. Pulmonary, splenic and resident peritoneal Il17ra-/- macrophages were significantly fewer than of wt origin. Bone marrow progenitor and monocyte numbers were equal, but the proportion of Il17ra-/-Gr1low monocytes was already decreased at bone marrow level. After monocyte depletion, initial Gr1high and Gr1low monocyte regeneration of Il17ra-/- and wt cells was very similar. However, Il17ra-/-Gr1low counts were not sustained. After labeling with either fluorescent beads or BrdU, Il17ra-/-Gr1high monocyte transition to Gr1low cells was not detectable unlike wt cells. Monocyte recruitment in acute peritonitis, which is known to be largely due to Gr1high cell migration, was unaffected in an identical environment. Unilateral ureteral obstruction induces a less acute inflammatory and fibrotic kidney injury. Compared to wt cells in the same environment, Il17ra-/- macrophage accumulation in the kidney was decreased. In the absence of Il17ra on all myeloid cells, renal fibrosis was significantly attenuated. Our data show that Il17ra modulates Gr1low monocyte counts and suggest defective Gr1high to Gr1low monocyte transition as an underlying mechanism. Lack of Il17ra altered homeostatic tissue macrophage formation and diminished renal inflammation and fibrosis. Il17ra appears to be a novel modulator of monocyte phenotype and possible therapeutic target in renal fibrosis.
Highlights
Monocytes are innate immune cells that frequently mediate early immune response [1,2,3]
We have previously demonstrated that IL-17 receptor A (Il17ra) that is required for both IL-17A and IL-17F [20], and IL-17C and IL-17E signaling is expressed [21,22]
To test for a role of IL-17 receptor A in monocyte homeostasis, we analyzed peripheral blood monocytes in wildtype and Interleukin 17 receptor A (Il17ra)-/- mice
Summary
Monocytes are innate immune cells that frequently mediate early immune response [1,2,3]. Life span is considerably longer than that of the other main innate myeloid cells, neutrophilic granulocytes, and monocytes can differentiate into macrophages with heterogeneous functions regarding cytokine production and antigen presentation in the target tissues. Two CD115 (M-CSF-receptor)+ monocyte subpopulations can be distinguished in mice [1,2,3]. Pharmacological blockade of the M-CSF receptor preferentially depletes Gr1low monocytes [7,8]. A number of observations suggest that most circulating Gr1low cells develop from Gr1high monocytes in the periphery [10,11,12]
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