CD83 expressed by macrophages is an important immune checkpoint molecule for the resolution of inflammation

Excessive macrophage (M phi) activation results in chronic inflammatory responses or autoimmune diseases. Therefore, identification of novel immune checkpoints on M phi, which contribute to resolution of inflammation, is crucial for the development of new therapeutic agents. Herein, we identify CD83 as a marker for IL-4 stimulated pro-resolving alternatively activated M phi (AAM). Using a conditional KO mouse (cKO), we show that CD83 is important for the phenotype and function of pro-resolving M phi. CD83-deletion in IL-4 stimulated M phi results in decreased levels of inhibitory receptors, such as CD200R and MSR-1, which correlates with a reduced phagocytic capacity. In addition, CD83-deficient M phi upon IL-4 stimulation, show an altered STAT-6 phosphorylation pattern, which is characterized by reduced pSTAT-6 levels and expression of the target gene Gata3. Concomitantly, functional studies in IL-4 stimulated CD83 KO M phi reveal an increased production of pro-inflammatory mediators, such as TNF-alpha, IL-6, CXCL1 and G-CSF. Furthermore, we show that CD83-deficient M phi have enhanced capacities to stimulate the proliferation of allo-reactive T cells, which was accompanied by reduced frequencies of Tregs. In addition, we show that CD83 expressed by M phi is important to limit the inflammatory phase using a full-thickness excision wound healing model, since inflammatory transcripts (e.g. Cxcl1, Il6) were increased, whilst resolving transcripts (e.g. Ym1, Cd200r, Msr-1) were decreased in wounds at day 3 after wound infliction, which reflects the CD83 resolving function on M phi also in vivo. Consequently, this enhanced inflammatory milieu led to an altered tissue reconstitution after wound infliction. Thus, our data provide evidence that CD83 acts as a gatekeeper for the phenotype and function of pro-resolving M phi.

Automated summary

This study identifies CD83 as a marker for IL-4 stimulated pro-resolving M phi and shows that CD83 is important for the phenotype and function of these M phi. CD83-deficient M phi exhibit reduced phagocytic capacity, altered STAT-6 phosphorylation pattern, increased production of pro-inflammatory mediators, enhanced stimulation of T cell proliferation, and altered tissue reconstitution after wound infliction.