IL-4 controls activated neutrophil FcγR2b expression and migration into inflamed joints

Abstract

Neutrophils are the most abundant immune cells found in actively inflamed joints of patients with rheumatoid arthritis (RA), and most animal models for RA depend on neutrophils for the induction of joint inflammation. Exogenous IL-4 and IL-13 protect mice from antibody-mediated joint inflammation, although the mechanism is not understood. Neutrophils display a very strong basal expression of STAT6, which is responsible for signaling following exposure to IL-4 and IL-13. Still, the role of IL-4 and IL-13 in neutrophil biology has not been well studied. This can be explained by the low neutrophil surface expression of the IL-4 receptor α-chain (IL-4Rα), essential for IL-4– and IL-13–induced STAT6 signaling. Here we identify that colony stimulating factor 3 (CSF3), released during acute inflammation, mediates potent STAT3-dependent neutrophil IL-4Rα up-regulation during sterile inflammatory conditions. We further demonstrate that IL-4 limits neutrophil migration to inflamed joints, and that CSF3 combined with IL-4 or IL-13 results in a prominent neutrophil up-regulation of the inhibitory Fcγ receptor (FcγR2b). Taking these data together, we demonstrate that the IL-4 and CSF3 pathways are linked and play important roles in regulating proinflammatory neutrophil behavior.

A rapid CRISPR competitive assay for in vitro and in vivo discovery of potential drug targets affecting the hematopoietic system

“…The Hoxb8 cells were generated by transducing BM cells of C57BL/6 Cas9 + GFP + mice with an estrogen-inducible retroviral construct expressing HOXB8 (ER-Hoxb8, a kind gift from Mark P. Kamps, University of California, San Diego) as described [26] , [27] . Transduced BM cells were cultured in 1 µM β-estradiol (BE, Sigma-Aldrich, #E2758) and 25 nM mouse SCF (PeproTech, #250–03) for several weeks with HOXB8 expression turned on to establish a cell line-like population.…”

Significance of Interleukin (IL)-4 and IL-13 in Inflammatory Arthritis

“…They observed diminished levels of IL-1β, TNF, IL-8, and prostaglandin E2 (PGE2) in RA ST explants upon the adenovirally delivered IL-4 [ 131 ]. In addition, in a recently performed study with K/BxN serum transfer model and a set of in vitro experiments, it was shown that IL-4 inhibits proinflammatory neutrophils activity and their migration to inflamed joints [ 132 ]. It was also observed that IL-4 displays the capacity to inhibit secretion of IL-11 proinflammatory cytokine by cultured synovial cells obtained from RA patients [ 133 ].…”

A rapid CRISPR competitive assay forin vitroandin vivodiscovery of potential drug targets affecting the hematopoietic system

“…The Hoxb8 cells were generated by transducing bone marrow cells of C57BL/6 Cas9+ GFP+ mice with an estrogen-inducible retroviral construct expressing HOXB8 (ER-Hoxb8, a kind gift from Mark P. Kamps, University of California, San Diego) as described [29,30]. Transduced BM cells were cultured in 1 µM β-estradiol (BE, Sigma-Aldrich, #E2758) and 25 nM mouse SCF (PeproTech, #250-03) for several weeks with HOXB8 expression turned on to establish a cell line-like population.…”