Progranulin Mediates Proinflammatory Response In The Pathogenesis Of Systemic Lupus Erythematosus

Background:Systemic lupus erythematosus(SLE)is an autoimmune disease characterized with multiple organ and multiple systemic injuries.Lupus nephritis(LN)is the most serious complication of SLE.About 20% of patients with LN may progress to uremia within 10 years,which seriously endangers human health and brings up heavy social burden.Therefore,it is imminent to identify the pathogenesis of SLE and find new therapeutic targets.PGRN is a multifunctional growth factor which was confirmed to play important roles in various pathophysiological processes,including immune regulation,injury repairment,inflammatory response and host defense in multiple studies.Earlier studies have demonstrated that PGRN promotes or inhibits the process of multiple diseases by regulating different signal pathways.It was reported that IFN-? plays important role in the development of SLE,an in our preliminary study we found that PGRNregulates the production of IRF1,an important transcription factor which regulates IFN-?.We also found that serum PGRN levels in patients with active SLE were significantly higher than normal controls,suggesting that PGRN may participate in the development of SLE,but the underlying mechanism is not unveiled.Objective:By synthesizing the preliminary results and literature,a hypothesis was promoted: By regulating the expression of IFN-?,PGRN promotes inflammation and exacerbates tissue injury in SLE and therefore accelerates the process of this disease.This study intends to verify this hypothesis by a detailed study into clinical example and gene deficiency animal model,by which provide novel experimental evidence for the mechanism of SLE pathogenesis and new strategy of immunotherapy against SLE.Methods:The concentrations of serum PGRN in pediatric and adult patients in the active phase of SLE were measured by enzyme-linked immunosorbent assay(ELISA).The mouse model of SLE was established by pristine in both wild type(WT)and PGRN-/-mice.The immunologic effects of SLE were evaluated by pathological damage of kidney,lung and spleen,the production of IFN-?and IFNAR,the alteration of T cell response and associated cytokine production and autoantibody production.Byobservation the tissue injury and inflammation of WT and PGRN-/-mice peritoneal injected with recombined IFN-?,we explored how PGRN affects the process of SLE.The associated signal pathway was explored by immunoblot.Results:Comparing to normal controls,serum PGRN levels of pediatric patients and adult patients with active SLE were significantly elevated.PGRN levels of peripheral blood and lung were also significantly increased in the SLE mouse model comparing to control group.Compared with WT mice,PGRN-/-mice demonstrated significant milder inflammatory cell infiltration,tissue edema,necrosis and other histopathological injuries in kidney,lung and spleen;lower level of IFN-? and IFNAR production,liver function damage markers including ALT,AST,and AST/ALT and renal function damage markers including BUN and Cr,which indicates that PGRN promotes SLE progress by elevating IFN-? production.Further,we found that IFNAR-/-mice with SLE showed significantly milder tissue injury and lower inflammation factor level,while the inflammation injury exacerbated when IFNAR-/-mice with SLE was peritoneal injected with recombined IFN-?,which agrees with the effect of PGRN deficiency,indicating that IFN-?promotes SLE progress in a similar manner with PGRN.Study into immune response demonstrated that PGRN deficiency lead to the unbalance of T cell(Th1,Th2 Th17 and Treg)and B cellresponse,thus lowered the production and inflammation factor(IFN-? and IL-17A)and autoantibodies(Anti-ds DNA,Anti-ribosomal P0),which agrees with the effect of PGRN,indicating that the harmful effect of PGRN in SLE is dependent on upregulating IFN-?.Conclusion:PGRN elevates IFN-?,enhances the Th1 cell response and promotes the production of autoantibodies while inhibits the differentiation of Treg cells,by which it led to the aggravation of inflammation and tissue damage and finally promotes the development of SLE.Thus,blocking PGRN may be a novel therapeutic strategy for SLE treatment.