DAMP-mediated inflammation and regulated cell death in immunoinflammatory rheumatic diseases

The state of autoreactivity of innate immunity dominates in the pathogenesis of immunoinflammatory rheumatic diseases, inducing non-infectious “sterile” inflammation. The distinctive properties of this inflammation include multiorgan affection and recurrent clinical course. The extracellular and intracellular “danger signals” called DAMPs, seem to be a key factor in progression of the inflammatory events. These factors are released by the loose fibrous connective tissue in the course of main substance disorganization, as well as regulated and accidental local cell death. In immune/inflammatory rheumatic diseases, the DAMP-induced patterns of regulated cell death include autophagy, apoptosis, necroptosis, pyroptosis and netosis. Membrane and cytosolic PRR receptors, interacting with DAMPs, promote these DAMP-induced forms of regulated cell death. At the same time, the DAMP-induced modes of regulated cell death are often combined with simultaneous reaction of PRR receptors to the pathogens that preexist in dead cells. TLR-DAMP interaction activates similar signaling pathways, adaptive molecules, transcription factors, forming the same pro-inflammatory inflammasomes as with TLR-PAMP interaction. In these processes, the antigen-presenting function of dendritic cells is expressed to the maximal extent. Given the important role of infections as etiological factors in immunoinflammatory rheumatic diseases, these processes may be the key factor inducing the phenomenon of antigenic cross-presentation. Interactions of DAMPs with PRR receptors of innate immunity cells cause the formation of a DAMP-mediated vicious circle. At the same time, increased levels of proinflammatory DAMPs, both in situ and in systemic circulation, leads, via the PRR-DAMP interactions, to incresing number of cells prone to regulated cell death and to even more pronounced tissue damage. In turn, these processes significantly increase the levels of pro-inflammatory DAMPs in tissues, thus causing progression of “sterile” inflammation to immunoinflammatory rheumatic diseases. The signaling pathways, adaptive molecules, transcription factors, and pro-inflammatory inflammasomes have been identified in all types of regulated cell death induced by PRR-DAMP interaction. The available research results allow us to determine appropriate targets which may be subjected to pharmacological correction. In thi