Regulatory Macrophages Inhibit Alternative Macrophage Activation and Attenuate Pathology Associated with Fibrosis.

Diversity and plasticity are the hallmarks of macrophages. The two most well-defined macrophage subsets are the classically activated macrophages (CAMϕs) and the IL-4-derived alternatively activated macrophages (AAMϕs). Through a series of studies, we previously identified and characterized a distinct population of macrophages with immunoregulatory functions, collectively termed regulatory macrophages (RMϕs). Although considerable advances have been made in understanding these various macrophage subsets, it is not known whether macrophages of one activation state can influence the other. In this study, we examined whether RMϕs capable of inhibiting inflammatory responses of CAMϕs could also inhibit AAMϕs and their profibrotic responses. Our results demonstrated that RMϕs significantly dampened the alternate activation phenotype of AAMϕs generated in vitro and intrinsically occurring AAMϕs from TACI-/- macrophages. Further, RMϕs inhibited AAMϕ-promoted arginase activity and fibroblast proliferation in vitro. This inhibition occurred regardless of the strength, duration, and mode of alternative activation and was only partially dependent on IL-10. In the chlorhexidine gluconate-induced peritoneal fibrosis model, AAMϕs worsened the fibrosis, but RMϕs rescued mice from AAMϕ-mediated pathological conditions. Taken together, our study demonstrates that RMϕs are a specialized subset of macrophages with a nonredundant role in limiting overt proregenerative functions of AAMϕs, a role distinct from their well-defined role of suppression of inflammatory responses by CAMϕs.

Key features of the innate immune response is mediated by the immunoproteasome in microglia.

Microglia are the resident immune cells of the central nervous system (CNS). We and others have shown that the inflammatory response of microglia is partially regulated by the immunoproteasome, an inducible form of the proteasome responsible for the generation of major histocompatibility complex (MHC) class I epitopes. While the role of the proteasome in the adaptive immune system is well established, emerging evidence suggests the immunoproteasome may have discrete functions in the innate immune response. Here, we show that inhibiting the immunoproteasome reduces the IFNγ-dependent induction of complement activator C1q, suppresses phagocytosis, and alters the cytokine expression profile in a microglial cell line and microglia derived from human inducible pluripotent stem cells. Moreover, we show that the immunoproteasome regulates the degradation of IκBα, a modulator of NF-κB signaling. Finally, we demonstrate that NADH prevents induction of the immunoproteasome, representing a potential pathway to suppress immunoproteasome-dependent immune responses.