Fibroblast tissue priming-not so nice to C you!

Abstract

The molecular mechanisms explaining why relapses of inflammatory arthritis occur at previously affected sites are unknown. In this issue of Immunity, Friščić et al. propose that local fibroblasts perpetuate inflammation after priming through cell-intrinsic complement C3, which reprograms their bioenergetics and activates the inflammasome.

Figure 1.. C3-dependent priming of fibroblasts (SFs) by danger sensing in synovial joints.

(A) naïve synovial fibroblasts (SFs) are activated and “primed” by repeated danger sensing. Phenotypically, this results in heightened and prolonged inflammation on repeat sensing of danger signals. (B) fibroblast priming events occurring within synovial tissue. Activation and priming of SFs induces chromatin remodeling and epigenetic changes that enhance accessibility at a number of loci encoding genes proteins mediating inflammation, bone remodeling, cellular metabolism and components of the complement system, including C3. The upstream signals required for transcription of C3 in SFs is currently unknown. C3 protein is enzymatically processed to activated fragments, including C3a and C3b. The enzymes mediating this process in SFs are not established. C3a ligands its cognate receptor, C3aR, either intracellularly and/or on the cell surface after secretion. Signaling mediated through the liganded receptor amplifies glycolysis and mTOR activation, and leads to inflammasome assembly. These result in secretion of inflammatory mediators, higher proliferative and invasive capacity of SFs and osteoclastogenesis.