Macrophages : as central inflammatory mediators and as targets for therapeutic interventions

Abstract

Macrophages (Mphis) are important cellular players in autoimmune pathogenesis, being the most numerous cells infiltrating sites of inflammation and causing much of the associated tissue damage. Apart from these proinflammatory actions, Mphis also have distinct roles in disease resolution, and effective therapeutic targeting of Mphi-expressed molecules requires understanding of the interplay between different Mphi activators and the kinetics of the induced responses.

While different Mphi subsets and activation states have been described, little is known about how Mphi properties vary between individuals/rodent strains with different susceptibility to autoimmune disease. We addressed this issue by comparing the activation patterns of rat BMMphis following stimulation by a panel of innate immunity stimulating agents in 3 inbred rat strains with different degrees of autoimmune susceptibility. Mphis from the autoimmune-susceptible strain were associated with alternative activation indicated by the induction of arginase activity, a lower production of classical proinflammatory mediators, and a higher production of IL-23. Conversely, Mphi from the autoimmuneresistant strains were associated with a higher production of proinflammatory mediators, a classical activation phenotype, and preferential induction of IL-12.

One known Mphi activator is HMGB1, and so we studied pathways activated by HMGB1 and investigated possible candidate Mphi receptors for this cytokine. Our results demonstrate that HMGB1 has the potential to induce a proinflammatory phenotype in primary rodent Mphis and that RAGE is an important, even though not the only, receptor for HMGB1 activation of Mphis.

As HMGB 1 plays an important role in several inflammatory diseases we studied its role in MS and EAE pathogeneses. Both MS and the animal model EAE was associated with significant up-regulation of HMGB1 and the receptors RAGE, TLR2 and TLR4. Primary microglia could also translocate HMGB1 both upon in vitro and in vivo stimulation. These data indicate involvement of HMGB1 in the pathogenesis of MS, and accordingly HMGB1 and its receptors are potential therapeutic targets in MS.

How initial innate immune activation through TLRs shapes the ensuing adaptive immune response that leads to organ-specific autoimmune disease is still poorly understood. We investigated the role of TLR6, TLR4 and TLR9 and the common TLR adaptor molecule Myd88 during induction of MOGEAE. Our data demonstrate that MyD88-signaling is crucial for the priming of TH-17 cells and hence for the induction of EAE. We also describe the regulation of Mphi IL-23 production by IFN-gamma. These data thus indicate the MyD88-signaling pathway and IFN-gammaR as other potential targets for therapeutic intervention in MS.