IL-33 Relieves Gout Inflammation By Inducing AAM Differentiation

Background Gouty arthritis(GA)is a common disease that is often caused by a disorder of purine metabolism or by an excretion of uric acid,that is an acute non-infective inflammatory response characterized by increased blood uric acid.The majority of the affected population are middle-aged and older males.The older,the higher the prevalence is,and the number of male patients is more than female.Gouty arthritis is characterized by an acute onset.The first episode most people have inflammatory symptoms in the first metatarsophalangeal joint,and within a day the inflammatory response such as redness and swelling pain can reach a peak,but usually after 1-2 weeks of attack Self-reliance,gouty arthritis if long-term repeated recurrence,may lead to joint deformities,kidney failure,kidney stones and other related diseases,so that the quality of life of patients significantly reduced.In recent decades,the incidence of gout disease in my past has been getting higher and higher,and the patient's age is also younger.IL-3 3 is a newly discovered cytokine belongs to the IL-1 superfamily.Its structure is similar to IL-18.Its receptor is ST2(also known as IL1RL1).IL-33 binding with ST2 and then activationdownstream signaling molecules,such as MyD88,can be recruited to activate NF-kB and MAPK signaling pathways,thereby activating extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinases and increasing the secretion of type 2 cytokines,such as IL-4,IL-5 and IL-13 and elicited Th2-type immune response.Through previous studies,we have found that the levels of IL-33 in the peripheral blood and joints of patients with gout are significantly increased,and IL-33 helps to relieve the gout caused by MSU in related experiments in gout model mice.However,the specific mitigation mechanism is not clearyet.It has been reported that type 2 macrophages(AAM)are involved in lipid metabolism and are associated with spontaneous remission of gout.Afteroard,we further found that IL-33 participates in the regulation of lipid metabolism in gout patients and plays a role in protecting renal function.It has been reported in the literature that alternative activated macrophages(AAMs or M2)are closely related to lipid metabolism and are also involved in the spontaneous remission of gout.We speculate that IL-33 may participate in the remission of gout by inducing AAM differentiation.Purposes To clear whether IL-33 participates in gout relief by inducing AAM.Methods 1.Obtain macrophages by inducing bone marrow cells differentiation in vitro.Add IL-4,IL-13,and IL-33 cytokines separately or IL4+IL-33,IL-13+IL-33in the medium of cells.After 48 hours of culture,the number of AAM cells was observed by flow cytometry.2.Using C57BL/6 mice as a model,intraperitoneal injections of IL-33 or PBS,continuous injected intraperitoneally for two days,and mice were sacrificed on the third day.Peritoneal lavage fluid cells were detected by flow cytometry to observe the changes of AAM cells;detecte the changes of cytokines IL-4,IL-5,and IL-13 in supernatant of peritoneal lavage fluid.3.The C57BL/6 mouse was used as a model and a balloon model was made on the back of them.The mice in the experimental group were injected intraperitoneally with IL-33,2ug,3 days before the balloon model was made,and the control group was injected with equal volume of PBS in the abdominal cavity.Once the ballon model was established,IL-33 or PBS was injected once again,and then decreased to small.Rats were intratracheally injected with MSU,3 mg/rat,and an acute gout model was established in mice.Mice were sacrificed 16 hours after injection of MSU.Mice were collected for balloon and peritoneal lavage fluid.AAM and neutrophils were detected by flow cytometry.The differences between the experimental group and the control group were observed.Results 1.IL-33 synergizes with IL-4 and IL-13 in vitro and indirectly promotes the differentiation of macrophages into AAM.2.Intraperitoneal injection of IL-33 cytokines in mice induced an increase in the number of F4/80 and CD206 double positiveAAM cells in peritoneal lavage fluid.3.The intraperitoneal injection of IL-33 cytokines in gout ballon mice induced an increase in F4/80 and CD206 double positive AAM cells in both ballon and peritoneal lavage fluid,also inhibits MSU-induced neutrophil infiltration.Conclusions Exogenous IL-33 induces the differentiation of macrophages into AAM cells and relieves gout inflammation by inducing an increase in the number of AAM cells.