The inflammatory architecture reflects the effects of pharmacological and genetic interventions on resolution of inflammation

During an innate immune response, immune cells form defined pro- and anti-inflammatory regions around a pathogen. These include, in toll-like receptor (TLR)-2-induced inflammation, a core region containing the pathogen, an adjacent pro-inflammatory (PI) region and a surrounding anti-inflammatory (AI) region. Interventions targeting specific immune cells or signaling pathways disrupt this architecture and affect the resolution of inflammation. Here, we investigated, which changes in the inflammatory architecture may favor an increased resolution of inflammation. Elimination of neutrophil recruitment using antibody depletion or GPR40-deficient mice had little effect on macrophage polarization and localization, formation of the inflammatory structure or resolution of inflammation, as determined by the duration and strength of thermal hypersensitivity. High content imaging and FACS analysis showed that macrophages and eosinophils compensated for the loss of neutrophils in pathogen phagocytosis. In contrast, G2A-deficient mice, which exhibit enhanced resolution of zymosan-induced hyperalgesia, have reduced macrophage recruitment and polarization as well as a shift in the inflammatory architecture towards anti-inflammation. Importantly, the reduction of M1-like macrophage polarization without reduction of macrophage numbers by the JAK1/2 inhibitor baricitinib was not sufficient to alter the inflammatory structure or resolution of inflammation. Combined with previously published results in the same inflammation model, we find that a strong decrease or increase of the PI region negatively impacts resolution of inflammation, whereas a moderate decrease seems to promote resolution of inflammation.