CN113318120A - Application of miR4512 and CXCL2 in autoimmune diseases - Google Patents

Abstract

Translated fromChinese

本发明公开了一种miR4512及CXCL2抗体在制备自身免疫性疾病的药物中的应用。所述的CXCL2抗体在制备改善狼疮鼠MRL/lpr的症状药物中的应用。所述的CXCL2抗体能减轻狼疮鼠的肾脏损害，包括：24小时尿蛋白的减少，肾脏病理的改善以及炎症细胞浸润的减少，同时能调控狼疮鼠MRL/lpr的ANA、ds‑DNA及细胞炎症因子(IL‑1β、IL‑2、IL‑4、IL‑6、IL‑10、IL‑12、TNF‑α、IFN‑γ和IL‑17)的分泌。

The invention discloses the application of miR4512 and CXCL2 antibody in preparing medicine for autoimmune diseases. The application of the CXCL2 antibody in the preparation of a medicine for improving the symptoms of MRL/lpr in lupus mice. The CXCL2 antibody can reduce kidney damage in lupus mice, including: reduction of 24-hour urine protein, improvement of renal pathology and reduction of inflammatory cell infiltration, and can regulate ANA, ds-DNA and cellular inflammation of MRL/lpr in lupus mice. Secretion of factors (IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, TNF-α, IFN-γ and IL-17).

Description

Application of miR4512 and CXCL2 in autoimmune diseases

Technical Field

The invention relates to the technical field of molecular biology and immunology, in particular to application of miR4512 and CXCL2 in autoimmune diseases.

Background

Autoimmune Diseases (AD) refers to a disease in which an organism immunoreacts with an autoantigen to cause damage to its own tissues. The exact pathogenesis of autoimmune diseases is unknown and is closely related to a variety of immunological abnormalities. Autoimmune diseases often have the following common features: the patients have obvious family tendentiousness, are related to HLA antigens, particularly D/DR gene loci, and are more female than male; ② the blood has high titer autoantibody and (or) sensitized lymphocyte which can react with self tissue component; ③ the diseases often show the processes of repeated attack and chronic persistence; fourthly, the causes of diseases are mostly unknown, and a few of the diseases are caused by medicines (immune hemolytic anemia, thrombocytopenic purpura), trauma (sympathetic ophthalmia) and the like; able to reproduce model similar to human autoimmune disease in experimental animal.

Systemic Lupus Erythematosus (SLE) is a common multi-system autoimmune disease. The exact etiology and pathogenesis of SLE has not yet been fully elucidated, and numerous studies have demonstrated that SLE patients have various types of inflammatory cell dysfunction. Under the interaction of various factors such as genetic factors, environmental factors, estrogen level and the like, T lymphocyte reduction, T suppressor cell function reduction and B cell hyperproliferation are caused, a large amount of autoantibodies are generated, and are combined with corresponding autoantigens in vivo to form corresponding immune complexes which are deposited on skin, joints, small blood vessels, glomeruli and other parts. In the presence of complement, acute and chronic inflammation and tissue necrosis (such as lupus nephritis, LN, or direct action of antibodies on histocyte antigens, and cell destruction caused by binding of specific antigens of erythrocyte, lymphocyte and platelet wall with corresponding autoantibodies, which cause hemolytic anemia, lymphopenia and thrombocytopenia, respectively, can result in multisystem damage to the body.

In systemic lupus erythematosus, SLE, patients with systemic involvement, kidney damage is most common. Studies show that when the Systemic Lupus Erythematosus (SLE) patient is subjected to renal puncture examination, almost all the patients have renal damage of different degrees, about 70 percent of the patients have obvious renal damage in the confirmed SLE, if the Systemic Lupus Erythematosus (SLE) patient is subjected to renal biopsy and the nephrosis is carried out, the renal damage can reach 90 percent, if immunofluorescence and electron microscopy are carried out, almost 100 percent of the patients have glomerular damage, if the treatment is not carried out in time, lupus nephritis can be developed finally, wherein about 20 percent of the patients have renal failure within 10 years, and the renal damage and the progressive renal damage are the main causes of death of the Systemic Lupus Erythematosus (SLE) patient. At present, the clinical treatment of patients with SLE and LN is mainly hormone, and is matched with an immunosuppressant, but the problems of infection, easy relapse and the like exist due to large dosage and long duration, and the life quality of the patients is seriously reduced. Therefore, there is an urgent need to find and research new potential therapeutic methods to obtain more precise targeted therapy, reduce the use of traditional drugs, and reduce side effects.

In order to further research and research the pathogenesis and potential treatment targets of SLE, blood samples of SLE patients are sequenced, the core effect of miR4512 in various immunoregulation signal channels is found, targets CXCL2 and TLR4 which are directly regulated and controlled are confirmed through dual-luciferase and cell experiments, the clinical samples are respectively verified, the miR4512 is found to be low-expressed in SLE patients, and target genes TLR4 and CXCL2 are highly expressed in SLE patients.

SLE has been reported to find that TLR4 is closely related to SLE, but no research on miR4512 at home and abroad is reported.

Disclosure of Invention

The present invention aims at the above problems, and provides a novel targeting mechanism for the key immunoregulatory pathway in autoimmune diseases, which directly acts on innate immune cells, and mainly comprises: immune inflammatory cells such as monocytes, macrophages and neutrophils are regulated by the miR-4512 to target a downstream TLR4-CXCL2 molecular pathway, so that inflammation activation is regulated, the generation of autoantibodies is reduced, and the application of the immune inflammatory cells in autoimmune diseases such as SLE is realized.

In order to achieve the purpose, the invention adopts the following technical scheme: the invention relates to application of miR4512 and CXCL2 antibodies in preparation of drugs for treating autoimmune diseases.

Furthermore, the CXCL2 antibody is applied to the preparation of kidney medicines for improving the MRL/lpr of lupus mice.

Further, the CXCL2 antibody can reduce kidney damage in lupus mice, comprising: the reduction of urine protein in 24 hours, the improvement of kidney pathology and the reduction of inflammatory cell infiltration can regulate and control the secretion of ANA, ds-DNA and cell inflammatory factors of MRL/lpr of lupus mice.

Further, the cell inflammatory factor is IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, TNF-alpha, IFN-gamma and IL-17; the CXCL2 antibody can reduce the formation of NETs, and can reduce the aggregation of neutrophils and monocytes in glomeruli, thereby reducing inflammation; the CXCL2 is a therapeutic target for SLE, LN and other autoimmune diseases.

Further, in the serum of the SLE patient, the miR-4512 shows low expression in both monocytes and lymphocytes of the SLE patient, and the target gene CXCL2 shows high expression; the low expression of miR-4512 can cause high expression of CXCL2 and TLR4, so that neutrophil activation is stimulated, and excessive formation or clearance of NETs is caused.

Further, the miR4512 can regulate the expression of a target gene CXCL 2.

Furthermore, the miR-4512 mainly plays a role in monocytes, and can be applied to autoimmune diseases such as SLE (systemic lupus erythematosus) by targeting CXCL2 antibody to regulate innate immune cells in the monocytes, wherein the innate immune cells are monocytes, macrophages or neutrophils, and regulating downstream TLR4-CXCL2 molecular pathway through miR-4512, so that inflammation activation is regulated, and generation of autoantibody is reduced.

Furthermore, the miR4512 participates in regulation and control of NETs related indexes, and inhibition of miR-4512 can increase expression of the NETs related indexes no matter the miR-4512 is a monocyte or a macrophage, while agonism of miR-4512 can cause reduction of expression of the NETs related indexes; in the neutrophil, the expression of miR-4512 in SLE patients with systemic lupus erythematosus has no obvious difference from normal control.

Further, this process may be associated with the TLR4/NF- κ B pathway, and miR-4512 in monocytes and macrophages in patients with systemic lupus erythematosus SLE may regulate NETS formation by targeting CXCL2 antibodies and various inflammatory factors to activate neutrophils, and participate in the development and progression of SLE.

Has the advantages that: CXCL2 and SLE are reported less frequently, and animal experiments for directly interfering CXCL2 on the influence of lupus diseases are not reported.

Drawings

FIG. 1 shows that at week 3 of treatment (11 weeks old mice) lupus mice in the treated group (MRL/lpr + CXCL2Ab) were significantly reduced compared to untreated lupus mice (MRL/lpr) and the difference was statistically significant (p < 0.01) after treatment with the CXCL2 antibody of the invention.

FIG. 2 shows that kidney pathology sections of lupus mice (MRL/lpr + CXCL2Ab) in the treatment group were compared with those of lupus mice (MRL/lpr) in the untreated group 4 weeks after treatment with the CXCL2 antibody of the present invention: glomerulonephritis cell infiltration is significantly reduced; the glomerular Activity Index (AI), the Chronic Index (CI) and the Tubular Index (TIL) in each section were evaluated quantitatively, and the renal pathology sections of lupus mice in the treated group (MRL/lpr + CXCL2Ab) were significantly down-regulated in both CI and TIL indices compared to lupus mice in the untreated group (MRL/lpr), with statistical differences (p < 0.05).

FIG. 3 significant differences in the downregulation of antinuclear antibodies (ANA) and double-stranded-DNA (ds-DNA) antibodies (P <0.05) in lupus mice in the treated group (MRL/lpr + CXCL2Ab) were statistically significant (p <0.05) over lupus mice in the untreated group (MRL/lpr) after 4 weeks of treatment with the CXCL2 antibody of the present invention.

FIG. 4 the kidney immunohistochemistry results of the present invention show: the levels of glomeruli CXCL2, CD45 and MPO in MRL/lpr mice were significantly higher than in C57 mice (p < 0.001); after 4 weeks of treatment with the CXCL2 antibody, the percentage of lupus mice in the treated group (MRL/lpr + CXCL2Ab) was significantly increased in the CXCL2 class i (degree of infiltration < 20%) and significantly decreased in the class iii (degree ofinfiltration 50% to 75%) (p < 0.0001) compared to the lupus mice in the untreated group (MRL/lpr); the proportion of CD45 grade I (infiltration degree is less than 20%) is obviously increased (p is less than 0.01); the proportion of MPO II grade (the infiltration degree is 25-50%) is increased (p is less than 0.0001).

FIG. 5 the ELISA of the present invention measures the levels of various cytokines in kidney and plasma: inflammatory factors in lupus mice in the treated group (MRL/lpr + CXCL2Ab) versus untreated group (MRL/lpr): the levels of IL-1 beta, IL-2, IL-6, IL-12, TNF-alpha, IFN-gamma and IL-17 are significantly reduced; IL-4 and IL-10 levels were significantly elevated (P < 0.05).

Detailed Description

For a better understanding of the invention, the following further illustrates the invention with reference to examples and drawings, but the invention is not limited to the following embodiments. The experimental methods used therein are conventional methods unless otherwise specified.

Example 1

As shown in fig. 1 to 5, the application of the miR4512 and CXCL2 antibodies of the present invention in the preparation of drugs for autoimmune diseases.

The CXCL2 antibody is applied to the preparation of a medicine for improving the symptoms of MRL/lpr of lupus mice.

The CXCL2 antibody can reduce kidney damage of lupus mice, and comprises the following components: the reduction of urine protein in 24 hours, the improvement of kidney pathology and the reduction of inflammatory cell infiltration can regulate and control the secretion of ANA, ds-DNA and cell inflammatory factors of MRL/lpr of lupus mice.

The cell inflammatory factor is IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, TNF-alpha, IFN-gamma and IL-17; the CXCL2 antibody can reduce the formation of NETs, and can reduce the aggregation of neutrophils and monocytes in glomeruli, thereby reducing inflammation; the CXCL2 is a therapeutic target for SLE, LN and other autoimmune diseases.

In the serum of a SLE patient with systemic lupus erythematosus, the miR-4512 has low expression in both monocytes and lymphocytes of the SLE patient with systemic lupus erythematosus, and the target gene CXCL2 has high expression; the low expression of miR-4512 can cause high expression of CXCL2 and TLR4, so that neutrophil activation is stimulated, and excessive formation or clearance of NETs is caused.

The miR4512 can regulate the expression of a target gene CXCL 2.

The miR-4512 mainly plays a role in monocytes, and regulates innate immune cells by targeting a CXCL2 antibody in the monocytes, wherein the innate immune cells are monocytes, macrophages or neutrophils, and regulates inflammation activation and reduces generation of autoantibodies through a TLR4-CXCL2 molecular pathway which is targeted to the downstream by regulation of miR-4512, so that the miR-4512 is applied to autoimmune diseases such as SLE (systemic Lupus erythematosus).

The miR4512 participates in regulation and control of NETs related indexes, and inhibition of miR-4512 can increase expression of the NETs related indexes no matter the miR-4512 is a monocyte or a macrophage, while activation of miR-4512 can reduce expression of the NETs related indexes; in the neutrophil, the expression of miR-4512 in SLE patients with systemic lupus erythematosus has no obvious difference from normal control.

This process may be associated with the TLR4/NF- κ B pathway, and miR-4512 in monocytes and macrophages in patients with Systemic Lupus Erythematosus (SLE) may regulate NETS formation by activating neutrophils via targeting CXCL2 antibodies and various inflammatory factors, and participate in the development and progression of SLE.

Test example 1

Study of miR4512

The expression of miR4512 and target genes (CXCL2 and TLR4) was verified in different cell lines: after the agonist (miR-4512agomir) and the inhibitor (miR-4512agomir) of miR-4512 and the Control thereof are used for transfecting Jurkat cells, BALL-1 cells and K562 cells for 48 hours respectively, Real-time PCR is used for detecting mRNA level changes of CXCL2 and TLR4 as target genes, and the results show that the mRNA expression quantity of the target genes (CXCL2 and TLR4) of the miR-4512agomir group is obviously lower than that of the miR-Control group, and the difference has statistical significance (p is less than 0.05); the expression level of miR-4512antagomir group target genes (CXCL2 and TLR4) is obviously higher than that of miR-Control group, and the difference has statistical significance (p is less than 0.01).

The expression conditions of miR-4512 and a target gene CXCL2/TLR4 of the miR-4512 in PBMCs, monocytes and neutrophils of a SLE patient with systemic lupus erythematosus are respectively verified.

The expression of miR-4512 and CXCL2/TLR4 mRNA in SLE patients/normal human PBMCs is detected by Q-PCR. The results show that: whether the SLE patient is a Tibetan SLE patient or a Han SLE patient, the expression of miR-4512 in the PBMCs of the human peripheral blood mononuclear cells is obviously reduced compared with a normal control, and the difference has statistical significance (p is less than 0.05). And (3) detecting the expression conditions of miR-4512 and CXCL2/TLR4 mRNA in SLE patients/normal human monocytes by Q-PCR. Whether the SLE patients are Tibetan systemic lupus erythematosus or Han systemic lupus erythematosus, the expression of miR-4512 in the monocytes is obviously reduced compared with a normal control, and the difference has statistical significance (p is less than 0.05). And (3) detecting the expression conditions of miR-4512 and CXCL2/TLR4 mRNA in SLE patients/normal human neutrophils through Q-PCR. No matter whether the SLE patients with Tibetan systemic lupus erythematosus or the SLE patients with Han systemic lupus erythematosus, the expression of miR-4512 in the sex granulocytes is not obviously different from the normal expression (p is less than 0.05).

After miR-4512 transfects mononuclear/macrophage, supernatant stimulates neutrophil and detects NETs related indexes, namely cfDNA: the expression of cfDNA in SLE patients with systemic lupus erythematosus is respectively detected by immunofluorescence, and the result shows that: the expression of cfDNA in SLE patients is obviously increased compared with normal people, and the difference has statistical significance (p is less than 0.01); MPO: the expression of MPO of SLE patients with systemic lupus erythematosus is respectively detected by ELISA, and the result shows that: the expression of MPO in SLE patients is obviously increased compared with normal people, and the difference has statistical significance (p is less than 0.05); NE expression in SLE patients with systemic lupus erythematosus was detected by Western-Blot. The results show that: the expression of NE in SLE patients with systemic lupus erythematosus is obviously higher than that of normal people, and the difference has statistical significance (p is less than 0.05).

After transfecting monocytes/macrophages of human serum with an agonist of miR-4512 (miR-4512agomir), an inhibitor of miR-4512 (miR-4512antagomir) and miR-4512-control (NC), respectively, 48 hours, the neutrophils isolated from healthy human serum were stimulated with the supernatant for 12 hours after transfection, and sequentially labeled as: the method comprises the following steps of carrying out amplification on a miR4512 agomir monocyte group, a miR4512antagomir monocyte group, a miR4512 agomir macrophage group and a miR4512antagomir macrophage group, observing the change condition of NETs through a laser confocal microscope, and respectively detecting the levels of cfDNA, NE and MPO.

The results show that: compared with normal control NC, the formation of NETs of the miR4512 agomir monocyte group is obviously reduced, and the expression of related indexes of the NETs is obviously reduced; the formation of NETs in the miR4512antagomir monocyte group is obviously increased, and the expression of related indexes of the NETs is obviously improved; compared with normal control NC, the formation of NETs in the miR4512 agomir macrophage group is obviously reduced, and the expression of related indexes of the NETs is obviously reduced; the formation of NETs in miR4512antagomir macrophage group is obviously increased, and the expression of related indexes of the NETs is obviously increased.

The improvement of the CXCL2 monoclonal antibody on the diseases of MRL/lpr lupus mice after treatment is clear: the change of the kidney function is evaluated by detecting the change condition of 24 small urine proteins every week, the Activity Index (AI), the Chronic Index (CI) and the renal tubule lesion index (TIL) of the kidney are evaluated by a full-scanning semi-quantitative method for a mouse renal disease slice after 4 weeks of intervention treatment, then the deposition condition of immune complexes in the kidney tissue is detected by adopting immunofluorescence staining, and then the anti-ds-DNA antibody and ANA antibody level in serum and the kidney tissue and the expression level of inflammatory factors in the blood and the kidney tissue are respectively detected by an ELISA method; immunohistochemical detection of changes in renal MPO, CXCL2, CD45 levels; immunofluorescence detects kidney IgG and C3 deposition.

The CXCL2 antibody can improve kidney damage after being used for treating MRL/lpr of lupus mice: the anti-CXCL2 group showed a significant reduction in proteinuria at 11 weeks (P < 0.01, see fig. 1) compared to the untreated group.

Antinuclear antibodies, double-stranded DNA antibodies (ds-DNA) and immunoinflammatory factor status in serum after CXCL2 treatment: after the anti-CXCL2 antibody is used for treating MRL/lpr mice, the anti-ds-DNA and ANA antibody levels in the blood plasma of lupus mice are obviously lower than those of non-intervention MRL/lpr mice (P < 0.001). Thus, anti-CXCL2 antibodies reduced serum immune markers of SLE. Detection of IL-1 β, IL-2, IL-4, IL-6, IL-10, IL-12, TNF- α, IFN- γ and IL-17 expression in kidney and plasma using ELISA: the CXCL2 antibody panel showed significantly reduced levels of IL-1 beta, IL-2, IL-6, IL-12, TNF-alpha, IFN-gamma and IL-17, and significantly increased levels of IL-4 and IL-10 in kidney and plasma (P < 0.05). Therefore, anti-CXCL2Ab regulates the secretion of inflammatory cytokines.

CXCL2 antibodies reduce NETs formation and reduce neutrophil and monocyte accumulation in the glomeruli. The invention further evaluates the treatment potential of antagonistic CXCL2 antibody on lupus murine MRL/lpr diseases by directly targeting the target gene CXCL2 of miR-4512.

Through repeated sequence comparison, miR-4512 is only expressed in a human body and is not expressed in a mouse, so that miR-4512 cannot be directly interfered in an animal body.

The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (9)

Translated fromChinese

1.一种miR4512及CXCL2抗体在制备自身免疫性疾病的药物中的应用。1. Application of miR4512 and CXCL2 antibodies in the preparation of medicines for autoimmune diseases.2.根据权利要求1所述的应用，其特征在于：所述的CXCL2抗体在制备改善狼疮鼠MRL/lpr的症状药物中的应用。2. The application according to claim 1, characterized in that: the application of the CXCL2 antibody in the preparation of a medicine for improving the symptoms of MRL/lpr in lupus mice.3.根据权利要求2所述的应用，其特征在于：所述的CXCL2抗体能减轻狼疮鼠的肾脏损害，包括：24小时尿蛋白的减少，肾脏病理的改善以及炎症细胞浸润的减少，同时能调控狼疮鼠MRL/lpr的ANA、ds-DNA及细胞炎症因子的分泌。3. application according to claim 2, it is characterized in that: described CXCL2 antibody can alleviate the kidney damage of lupus mouse, comprise: the reduction of 24 hours urine protein, the improvement of kidney pathology and the reduction of inflammatory cell infiltration, can simultaneously. Regulates the secretion of ANA, ds-DNA and cellular inflammatory factors of MRL/lpr in lupus mice.4.根据权利要求2所述的应用，其特征在于：所述的细胞炎症因子为IL-1β、IL-2、IL-4、IL-6、IL-10、IL-12、TNF-α、IFN-γ或IL-17；所述的CXCL2抗体能减少NETs的形成，可降低肾小球中中性粒细胞和单核细胞的聚集，从而减轻炎症；所述的CXCL2为SLE、LN及其他自身免疫性疾病的治疗靶标。4. application according to claim 2 is characterized in that: described cellular inflammatory factor is IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, TNF-α, IFN-γ or IL-17; the CXCL2 antibody can reduce the formation of NETs, can reduce the aggregation of neutrophils and monocytes in the glomerulus, thereby reducing inflammation; the CXCL2 is SLE, LN and other Therapeutic targets in autoimmune diseases.5.根据权利要求2所述的应用，其特征在于：系统性红斑狼疮SLE患者血清中，所述的miR-4512在系统性红斑狼疮SLE患者的单核细胞和淋巴细胞中均呈低表达，其靶基因CXCL2均呈高表达；miR-4512的低表达能导致CXCL2和TLR4的高表达，从而刺激中性粒细胞激活，导致NETs的形成过多或清除障碍。5. application according to claim 2, it is characterized in that: in the serum of SLE patient of systemic lupus erythematosus, described miR-4512 in the monocyte and lymphocyte of systemic lupus erythematosus SLE patient all show low expression, Its target gene CXCL2 is highly expressed; the low expression of miR-4512 can lead to the high expression of CXCL2 and TLR4, thereby stimulating the activation of neutrophils, resulting in excessive formation or clearance of NETs.6.根据权利要求2所述的应用，其特征在于：所述的miR4512可以调节靶基因CXCL2的表达。6. The application according to claim 2, wherein the miR4512 can regulate the expression of the target gene CXCL2.7.根据权利要求1所述的应用，其特征在于：所述的miR-4512主要在单核细胞中发挥作用，通过在单核细胞中靶向CXCL2抗体调节固有免疫细胞，所述的先天性的免疫细胞为单核细胞、巨噬细胞或中性粒细胞，通过miR-4512的调节靶向下游的TLR4-CXCL2分子通路，调节炎症激活，降低自身抗体的产生，从而应用于SLE等自身免疫性疾病中。7. The application according to claim 1, wherein the miR-4512 mainly plays a role in monocytes, and regulates innate immune cells by targeting CXCL2 antibodies in monocytes, and the innate The immune cells are monocytes, macrophages or neutrophils. Through the regulation of miR-4512, they target the downstream TLR4-CXCL2 molecular pathway, regulate inflammatory activation, and reduce the production of autoantibodies, thus being applied to autoimmunity such as SLE. in sexually transmitted diseases.8.根据权利要求1所述的应用，其特征在于：所述的miR4512参与NETs相关指标的调控，无论是单核细胞还是巨噬细胞，抑制miR-4512均能使与NETs相关指标的表达升高，而激动miR-4512会导致与NETs相关的指标表达降低；而在中性粒细胞中，所述的miR-4512在系统性红斑狼疮SLE患者中的表达与正常对照无明显差异。8. The application according to claim 1, wherein: the miR4512 is involved in the regulation of NETs-related indexes, and whether it is a monocyte or a macrophage, inhibiting miR-4512 can increase the expression of NETs-related indexes. However, in neutrophils, the expression of miR-4512 in patients with systemic lupus erythematosus SLE was not significantly different from that in normal controls.9.根据权利要求1所述的应用，其特征在于：这一过程可能与TLR4/NF-κB通路有关，系统性红斑狼疮SLE患者体内的单核细胞和巨噬细胞中的miR-4512可能通过靶向CXCL2抗体和多种炎症因子激活中性粒细胞从而调控NETs的形成，参与SLE的发生和发展。9. The application according to claim 1, characterized in that: this process may be related to the TLR4/NF-κB pathway, and miR-4512 in monocytes and macrophages in patients with systemic lupus erythematosus (SLE) may pass through. Targeting CXCL2 antibodies and various inflammatory factors activate neutrophils to regulate the formation of NETs and participate in the occurrence and development of SLE.

Images