Interleukin 17A controls Interleukin 17F production to maintain precise regulation of blood neutrophil counts in mice (133.8)

Abstract

Abstract Granulocyte colony-stimulating factor (G-CSF), its receptor and interleukin-17 receptor A (IL-17RA) are all required to maintain baseline neutrophil counts in mice. Here, we tested whether IL-17F could compensate and maintain baseline neutrophil counts in the absence of IL-17A. Unlike the reduced neutrophil counts found in IL-17RA deficient mice, neutrophil counts were mildly increased in IL-17A deficient (Il17a-/-) animals. There was no evidence for infection or altered neutrophil function. Plasma G-CSF and IL-17F levels were elevated in Il17a-/- compared to wild-type mice. IL-17F was mainly produced in the spleen and mesenteric lymph nodes, but IL-23 was unaltered in Il17a-/- mice. Instead, Il17a-/- splenocytes differentiated with IL-6, TGF-β and IL-23 ex-vivo produced significantly more IL-17F in response to IL-23 than wild-type cells. Adding recombinant IL-17A to Il17a-/-splenocyte cultures reduced IL-17F mRNA and protein secretion. These effects were also observed in wild-type but not IL-17RA deficient cells. We conclude that IL-17A mediated suppression of IL-17F production and secretion is relevant to maintain the normal setpoint of blood neutrophil counts in vivo.