Interleukin 17 receptor A modulates monocyte subsets and macrophage generation in vivo

Shuwang Ge; Barbara Hertel; Nathan Susnik; Song Rong; Anna M Dittrich; Roland Schmitt; Hermann Haller; Sibylle von Vietinghoff

doi:10.1371/journal.pone.0085461

Interleukin 17 receptor A modulates monocyte subsets and macrophage generation in vivo

PLoS One. 2014 Jan 15;9(1):e85461. doi: 10.1371/journal.pone.0085461. eCollection 2014.

Authors

Shuwang Ge¹, Barbara Hertel², Nathan Susnik², Song Rong², Anna M Dittrich³, Roland Schmitt², Hermann Haller², Sibylle von Vietinghoff²

Affiliations

¹ Department of Medicine, Hannover Medical School, Hannover, Germany ; Department of Nephrology, Tongji Hospital, Huazhong University, Wuhan, China.
² Department of Medicine, Hannover Medical School, Hannover, Germany.
³ Department of Pediatrics, Hannover Medical School, Hannover, Germany.

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(-/-) Gr1(low) 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(-/-) Gr1(low) monocytes was already decreased at bone marrow level. After monocyte depletion, initial Gr1(high) and Gr1(low) monocyte regeneration of Il17ra(-/-) and wt cells was very similar. However, Il17ra(-/-) Gr1(low) counts were not sustained. After labeling with either fluorescent beads or BrdU, Il17ra(-/-) Gr1(high) monocyte transition to Gr1(low) cells was not detectable unlike wt cells. Monocyte recruitment in acute peritonitis, which is known to be largely due to Gr1(high) 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 Gr1(low) monocyte counts and suggest defective Gr1(high) to Gr1(low) 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
DNA Primers
Homeostasis
Macrophages / cytology*
Mice
Mice, Inbred C57BL
Monocytes / cytology*
Real-Time Polymerase Chain Reaction
Receptors, Interleukin-17 / genetics
Receptors, Interleukin-17 / physiology*

Substances

DNA Primers
Receptors, Interleukin-17

Grants and funding

Shuwang Ge was supported by National Science Foundation of China (No. 81200531) and Sibylle von Vietinghoff by Deutsche Forschungsgemeinschaft (www.dfg.de) Grant VI 508/4-1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.