Iron is an essential nutrient, but excessive amounts can be toxic. Consequently, tight regulation of iron-homeostasis has evolved. Iron accumulation was demonstrated in inflamed tissue-lesions of patients with chronic inflammation, suggesting an inflammation-induced dysregulation of iron homeostasis. Based on this observation, we propose that impaired iron regulation influences the course of inflammation. To test this hypothesis, inflammatory response was studied in bone marrow-derived macrophages (BMDM) from mice with targeted deletions of the iron regulatory proteins (Irp)1 or Irp2, and in mouse models for rheumatoid arthritis (RA) as well as in uropathogenic Escherichia coli (UPEC) mediated epididymo-orchitis. 

Irp1-/- BMDM showed a weaker, and Irp2-/- BMDM showed a stronger response to inflammation as demonstrated by the activation of the “mitogen-activated protein kinases” (MAPK) signaling pathways and inflammatory cytokine-production (Tnfα, Il-6). Following induction of inflammation, Seahorse analysis revealed differences in energy metabolism suggesting a more anti-inflammatory phenotype (M2) for Irp1-/- BMDM, and a more pro-inflammatory phenotype (M1) for Irp2-/- BMDM. Similarly, UPEC-mediated epididymo-orchitis elicited a significantly lower production of inflammatory cytokines (Tnfα, Il-6, Il1-β) and chemokines (Cxcl2, Ccl2) in the testis of Irp1-/- mice. In contrast, following infection, neutrophil-infiltration increased in the testis of Irp2-/- mice. Furthermore, deletion of Irp1, in a mouse model for Crohn’s disease and RA, completely abolished the intestinal inflammation, and reduced the inflammation in the joints.

Our data suggest opposing inflammatory responses of Irp1 and Irp2, and shed light on the intricate interplay between Irp1 and Irp2, cellular iron metabolism, energy metabolism, and macrophage polarization during inflammation.