Extraordinarily potent proinflammatory properties of lactoferrin-containing immunocomplexes against human monocytes and macrophages.

Lactoferrin (LTF)， an important first line defense molecule against infection， is a common target for humoral autoimmune reactions in humans. Since LTF is a multifunctional protein capable of activating innate immune cells via various surface receptors， we hypothesized that LTF-containing immune complexes (ICs) (LTF-ICs)， likely formed in patients with high titer anti-LTF autoantibodies， could possess unique monocyte/macrophage-activating properties compared with other ICs. ELISA analysis on serum samples from rheumatoid arthritis (RA) patients (n?=?80) and healthy controls (n?=?35) for anti-LTF autoantibodies confirmed a positive correlation between circulating LTF-specific IgG and RA. ICs between human LTF and LTF-specific IgG purified from patient sera or immunized rabbits and mice， but not control ICs， LTF or Abs alone， elicited strong production of TNF-α and IL-1β by freshly fractionated human peripheral blood monocytes and monocytes-derived macrophages. Furthermore， LTF-ICs utilized both membrane-anchored CD14 and CD32a (FcγRIIa) to trigger monocyte activation in an internalization-， Toll-like receptor (TLR)4- and TLR9-dependent manner， and also that LTF-IC-induced cytokine production was blocked by specific inhibitors of caspase-1， NF-κB and MAPK. These results uncover a possible pathway for LTF-ICs perpetuating local inflammation and contributing to the pathogenesis of autoimmune diseases by triggering activation of infiltrating monocytes or tissue macrophages in vivo.