Role of granulocytes activation in the pathogenesis of Systemic juvenile idiopathic arthritis and Adult onset Still’s disease

The autoinflammatory syndromes are a group of disorders defined as “unmotivated recurrent inflammatory events” haracterized by an apparently spontaneous manifestations of inflammation, without autoreactive T cells or auto-antibody involvement. These conditions usually present aberrant responses associated to molecular pathogenic patterns and deregulated production of inflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-18 (IL-18) and Tumor Necrosis Factor-α (TNF- α). Systemic juvenile idiopathic arthritis (sJIA) and Adult onset Still’s disease (AOSD) are particular kinds of autoinflammatory disorders with still unknown etiology, mainly associated to the possible pathogenic role of IL-1β, since the efficiency of pharmacological treatments with IL-1β blockers agents. The typical patients’ neutrophilia would presume the PMNs involvement at the onset of these syndromes. For this reason we have analyzed the PMNs activation state at baseline, together with their response to extracellular pro-inflammatory stimuli. In comparison with healthy granulocytes, sJIA and AOSD PMNs didn’t present differences in term of cellular activation state and IL-1β production, and our results also revealed that neither healthy nor sJIA/AOSD PMNs can produce elevated levels of this cytokine, as opposed to monocytes, which can release IL-concentrations more than 10 fold higher than PMNs. We have also analyzed the inflammatory response mediated by monocytes, after activation of three different inflammasome complexes, in sJIA, AOSD patients and patients affected by the hereditary periodic fever syndromes (HPFs) Familial Mediterranean Fever (FMF) and Cryopyrin associated periodic syndrome (CAPS). Monocytes from HPFs affected patients have shown the clear involvement of one specific inflammasome complex. sJIA and AOSD monocytes, instead, have not presented significant differences with healthy monocytes, leaving some doubts about the principal cellular source of IL-1β in these syndromes, also considering previous experiments which indicated that sJIA monocytes released even lower IL-1β concentrations than healthy monocytes. An important difference has been observed about the S100 calcium-binding protein A12 (S100A12) production. Indeed, patients PMNs have produced higher levels of S100A12 after stimulation in comparison with healthy ones. This result could be related to the typical elevated S100A12 serum concentration observed in affected patients. Taken together, our observations indicate that the role of PMNs in sJIA and AOSD is not directly related to the inflammasome activity and IL-1β production, but it deserves further investigations about a possible different action mechanism, involved in the pathogenesis of these syndromes.