Interleukin 17 Receptor A Modulates Monocyte Subsets and Macrophage Generation In Vivo

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.

Innate Lymphocyte/Ly6C hi Monocyte Crosstalk Promotes Klebsiella Pneumoniae Clearance

“…While one of the major functions of IL-17 is facilitating neutrophil recruitment (Kolls and Linden, 2004; Ye et al, 2001), its impact on IM recruitment and activation has been less clear. Previous studies demonstrated IL-17R expression on mouse and human monocytes, and that IL-17 signaling can regulate their differentiation and migration (Ge et al, 2014; Shahrara et al, 2009). We found high IL-17R expression by lung IMs, and demonstrate that IL-17 signaling enhances bacterial phagocytosis and killing by IMs.…”

Nonclassical Patrolling Monocyte Function in the Vasculature

“…CX3CR1 −/− mice have fewer circulating Ly6C − monocytes, which has been attributed to reduced monocyte survival resulting from CX3CR1-dependent expression of the anti-apoptotic protein BCL2 42 . In this context it is interesting to note that global IL17RA-deficiency leads to a similar reduction in Ly6C − monocyte survival 43 , and that BCL2 is an IL17 target gene in fibroblast-like synoviocytes 44 . However a causal link between IL17RA-dependent signaling and BCL2 expression in patrolling monocytes has not been established.…”

Dendritic Cells and Macrophages

“…Mechanistically, activated macrophages secreted reactive oxygen species and proinflammatory cytokines, which induced apoptosis of tubular epithelial cells and stimulated interstitial fibroblasts to deposit extracellular matrix, leading to kidney fibrosis (82,83). Several macrophage-activating receptors have been described with inhibition that may be of therapeutic value in nonimmune CKD (84)(85)(86) (Table 2).…”