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

Abstract

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 this respect, significant  progress  has been  made  in search  for medicinal tools  of regulating inflammation in SLE,  RA, Sjogren’s syndrome, SSD,  etc. Of sufficient  importance are both evaluation of serum DAMP levels as diagnostic and prognostic biomarkers, along with their  determination for assessing treatment efficiency  in immunoinflammatory rheumatic diseases.