Differential macrophage expression of IL‐12 and IL‐23 upon innate immune activation defines rat autoimmune susceptibility

Rodents typically demonstrate strain‐specific susceptibilities to induced autoimmune models such as experimental arthritis and encephalomyelitis. A common feature of the local pathology of these diseases is an extensive infiltration of activated macrophages (MΦ). Different functional activation states can be induced in MΦ during innate immune activation, and it is this differential activation that might be important in susceptibility/resistance to induction or perpetuation of autoimmunity. In this study, we present an extensive, comparative analysis of the activation phenotypes of MΦ derived from autoimmune‐susceptible and autoimmune‐resistant rat strains to describe a cellular phenotype that defines the disease phenotype. We included investigation of receptor function, intracellular signaling pathways, cytokines, and other soluble mediators released after activation of cells using a panel of stimuli embracing many activation routes. We report that activation of MΦ from the autoimmune‐susceptible strain was associated with alternative activation indicated by induction of arginase activity, a lower production of classical proinflammatory mediators, and a high production of interleukin (IL)‐23, and MΦ from the autoimmune‐resistant strains were associated with a higher production of proinflammatory mediators, a classical activation phenotype, and preferential induction of IL‐12. These MΦ phenotypes thus reflect disparate, genetic cellular programs that define autoimmune susceptibility.