CCR2‐dependent Gr1high monocytes promote kidney injury in shiga toxin‐induced hemolytic uremic syndrome in mice

The hemolytic uremic syndrome (HUS) is a life‐threatening disease of the kidney that is induced by shiga toxin‐producing E.coli. Major changes in the monocytic compartment and in CCR2‐binding chemokines have been observed. However, the specific contribution of CCR2‐dependent Gr1^high monocytes is unknown. To investigate the impact of these monocytes during HUS, we injected a combination of LPS and shiga toxin into mice. We observed an impaired kidney function and elevated levels of the CCR2‐binding chemokine CCL2 after shiga toxin/LPS‐ injection, thus suggesting Gr1^high monocyte infiltration into the kidney. Indeed, the number of Gr1^high monocytes was strongly increased one day after HUS induction. Moreover, these cells expressed high levels of CD11b suggesting activation after tissue entry. Non‐invasive PET‐MR imaging revealed kidney injury mainly in the kidney cortex and this damage coincided with the detection of Gr1^high monocytes. Lack of Gr1^high monocytes in Ccr2‐deficient animals reduced neutrophil gelatinase‐associated lipocalin and blood urea nitrogen levels. Moreover, the survival of Ccr2‐deficient animals was significantly improved. Conclusively, this study demonstrates that CCR2‐dependent Gr1^high monocytes contribute to the kidney injury during HUS and targeting these cells is beneficial during this disease.     

The oxidative stress induced in vivo by Shiga toxin‐2 contributes to the pathogenicity of haemolytic uraemic syndrome

Typical haemolytic uraemic syndrome (HUS) is caused by Shiga toxin (Stx)‐producing Escherichia coli infections and is characterized by thrombotic microangiopathy that leads to haemolytic anaemia, thrombocytopenia and acute renal failure. Renal or neurological sequelae are consequences of irreversible tissue damage during the acute phase. Stx toxicity and the acute inflammatory response raised by the host determine the development of HUS. At present there is no specific therapy to control Stx damage. The pathogenic role of reactive oxygen species (ROS) on endothelial injury has been largely documented. In this study, we investigated the in‐vivo effects of Stx on the oxidative balance and its contribution to the development of HUS in mice. In addition, we analysed the effect of anti‐oxidant agents as therapeutic tools to counteract Stx toxicity. We demonstrated that Stx induced an oxidative imbalance, evidenced by renal glutathione depletion and increased lipid membrane peroxidation. The increased ROS production by neutrophils may be one of the major sources of oxidative stress during Stx intoxication. All these parameters were ameliorated by anti‐oxidants reducing platelet activation, renal damage and increasing survival. To conclude, Stx generates a pro‐oxidative state that contributes to kidney failure, and exogenous anti‐oxidants could be beneficial to counteract this pathogenic pathway.     

Delayed post‐injury administration of C5a improves regeneration and functional recovery after spinal cord injury in mice

The activation of a complement system can aggravate the secondary injury after spinal cord injury (SCI). However, it was reported recently that the activation of a complement could have both a secondary injury and a neuroprotective effect, in which C5a is the most important factor, but there is no direct evidence for this dual effect of C5a after SCI. In order to investigate the potential neuroprotective effect of C5a after SCI, in this study ectogenic C5a was injected intraperitoneally before/after SCI in vivo, or administrated to mechanically injured neurones in vitro; following this, neurone apoptosis, neurite outgrowth, axonal regeneration and functional recovery were investigated. The in‐vivo experiments indicated that, following treatment with C5a 24 h before or immediately after injury, locomotor function was impaired significantly. However, when treatment with C5a took place 24 h after injury, locomotor function improved significantly. In‐vitro experiments indicated that a certain concentration of C5a (50–100 nM) could inhibit caspase‐3‐mediated neurone apoptosis by binding to its receptor CD88, and that it could even promote the neurite outgrowth of uninjured neurones. In conclusion, delayed post‐injury administration of C5a within a certain concentration could exert its neuroprotective effect through inhibiting caspase‐3‐mediated neurone apoptosis and promoting neurite outgrowth of uninjured neurones as well. These data suggest that C5a may have opposite functions in a time‐ and concentration‐dependent manner after SCI. The dual roles of C5a have to be taken into account when measures are taken to inhibit complement activation in order to promote regeneration after SCI.     

Curcumin alleviates immune‐complex‐mediated glomerulonephritis in factor‐H‐deficient mice

Complement factor H (Cfh) is a key regulator of the complement cascade and protects C57BL/6 mice from immune complex-mediated complement-dependent glomerulonephritis. In chronic serum sickness (CSS) there are increased deposits of immune complexes in the glomeruli with inflammation and a scarring phenotype. As cucurmin is an effective anti-inflammatory agent and reduces complement activation, we hypothesized that it should alleviate renal disease in this setting. To determine the effectiveness of curcumin, an apoferritin-induced CSS model in Cfh-deficient (Cfh^−/−) mice was used. Curcumin treatment (30 mg/kg) given every day in parallel with apoferritin reduced glomerulonephritis and enhanced kidney function (blood urea nitrogen, 45·4 ± 7·5 versus 35·6 ± 5·1; albuminuria, 50·1 ± 7·1 versus 15·7 ± 7·1; glomerulonephritis, 2·62 + 0·25 versus 2 + 0·3, P < 0·05). In line with reduced IgG deposits in mice with CSS given curcumin, C9 deposits were reduced indicating reduced complement activation. Mice treated with curcumin had a significant reduction in the number of splenic CD19⁺ B cells and the ratio of CD19 : CD3 cells (P < 0·05) with no change in the T-cell population. Myeloperoxidase assay showed reduced macrophages in the kidney. However, a significant reduction in the M2 subset of splenic macrophages by apoferritin was prevented by curcumin, suggesting a protective function. Curcumin treatment reduced mRNA expression of inflammatory proteins monocyte chemoattractant protein-1 and transforming growth factor-β and matrix proteins, fibronectin, laminin and collagen. Our results clearly illustrate that curcumin reduces glomerulosclerosis, improves kidney function and could serve as a therapeutic agent during serum sickness.     

Lowered albumin extravasation rate in heart but not in other organs in β3‐integrin‐deficient mice

Aim: The vascular protein permeability is dependent on the integrity of the vascular wall. The heart capillaries in male mice lacking β3 integrins have an immature phenotype. Previously, we have demonstrated a role for αvβ3 integrins in control of interstitial fluid pressure (Pif) and thereby in the fluid flux during inflammation. We wanted to explore a possible role for αvβ3 integrins in controlling capillary protein permeability during control situation and inflammation. Methods: We performed double‐tracer and microdialysis experiments on β3‐integrin‐deficient mice and wild type control mice. We also measured blood pressure and heart rate in the two mice strains. Results: We found reduced albumin extravasation (during 25 min) in the heart capillaries (0.053 ± 0.003 vs. 0.087 ± 0.009 mL g^?1 dw, P < 0.05), and an increased cardiac mass/body weight (5.3 × 10^?3 ± 0.3 × 10^?3 vs. 3.8 × 10^?3 ± 0.1 × 10^?3, P < 0.01) in the β3‐integrin‐deficient mice (n = 6) compared with the controls (n = 6). Heart rate and blood pressure were the same in mice with and without β3‐integrins. No difference in permeability was found in other tissues studied, or under local inflammation. Conclusion: These results show a function for the αvβ3 integrin in the regulation of protein permeability, selective for the heart capillaries.     

MASP2 levels are elevated in thrombotic microangiopathies: association with microvascular endothelial cell injury and suppression by anti‐MASP2 antibody narsoplimab

Involvement of the alternative complement pathway (AP) in microvascular endothelial cell (MVEC) injury characteristic of a thrombotic microangiopathy (TMA) is well documented. However, the role of the lectin pathway (LP) of complement has not been explored. We examined mannose‐binding lectin associated serine protease (MASP2), the effector enzyme of the LP, in thrombotic thrombocytopenic purpura, atypical hemolytic uremic syndrome and post‐allogeneic hematopoietic stem cell transplantation (alloHSCT) TMAs. Plasma MASP2 and terminal complement component sC5b‐9 levels were assessed by enzyme‐linked immunosorbent assay (ELISA). Human MVEC were exposed to patient plasmas, and the effect of the anti‐MASP2 human monoclonal antibody narsoplimab on plasma‐induced MVEC activation was assessed by caspase 8 activity. MASP2 levels were highly elevated in all TMA patients versus controls. The relatively lower MASP2 levels in alloHSCT patients with TMAs compared to levels in alloHSCT patients who did not develop a TMA, and a significant decrease in variance of MASP2 levels in the former, may reflect MASP2 consumption at sites of disease activity. Plasmas from 14 of the 22 TMA patients tested (64%) induced significant MVEC caspase 8 activation. This was suppressed by clinically relevant levels of narsoplimab (1·2 μg/ml) for all 14 patients, with a mean 65·7% inhibition (36.8–99.4%; P < 0·0001). In conclusion, the LP of complement is activated in TMAs of diverse etiology. Inhibition of MASP2 reduces TMA plasma‐mediated MVEC injury in vitro. LP inhibition therefore may be of therapeutic benefit in these disorders.     

C‐terminal deletion of the atrophin‐1 protein results in growth retardation but not neurodegeneration in mice

Dentatorubral‐pallidoluysian atrophy (DRPLA) is a dominant hereditary neurodegenerative disorder caused by the expansion of a poly‐glutamine (poly‐Q) repeat in Atrophin‐1 protein. Ectopic expression of a poly‐Q expanded human Atrophin‐1 is sufficient to induce DRPLA phenotypes in mice. However, it is still unclear whether the dominant effect of poly‐Q expansion is due to the functional interference with wild‐type Atrophin‐1 proteins, which exist in both patients and transgenic mice. Here we report the generation and analysis of an Atrophin‐1 targeting allele that expresses a truncated protein lacking both the poly‐Q repeat and following C‐terminal peptides. Homozygous mutants exhibit growth retardation and progressive male infertility, but no obvious signs of neurodegeneration. Moreover, the mutant allele neither blocked nor enhanced the neurodegenerative phenotypes caused by a poly‐Q expanded transgene. These results support the model that poly‐Q expanded Atrophin‐1 proteins cause DRPLA in a manner independent of any functional interaction with wild‐type Atrophin‐1 proteins. Developmental Dynamics 238:2471–2478, 2009. © 2009 Wiley‐Liss, Inc.     

Ccl2/Mcp‐1 blockade reduces glomerular and interstitial macrophages but does not ameliorate renal pathology in collagen4A3‐deficient mice with autosomal recessive Alport nephropathy

Lack of the α3 or α4 chain of type IV collagen (COL4) causes autosomal recessive Alport nephropathy in humans and mice that is characterized by progressive glomerulosclerosis and tubulointerstitial disease. Renal pathology is associated with chemokine‐mediated macrophage infiltrates but their contribution to the progression of Alport nephropathy is unclear. We found Ccl2 to be expressed in increasing amounts during the progression of nephropathy in Col4a3‐deficient mice; hence, we blocked Ccl2 with anti‐Ccl2 Spiegelmers, biostable L ‐enantiomeric RNA aptamers suitable for in vivo applications. Ccl2 blockade reduced the recruitment of ex vivo‐labelled macrophages into kidneys of Col4a3‐deficient mice. We therefore hypothesized that a prolonged course of Ccl2 blockade would reduce renal macrophage counts and prevent renal pathology in Col4a3‐deficient mice. Groups of Col4a3‐deficient mice received subcutaneous injections of either an anti‐mCcl2 Spiegelmer or non‐functional control Spiegelmer on alternate days, starting from day 21 or 42 of age. Glomerular and interstitial macrophage counts were found to be reduced with Ccl2 blockade by 50% and 30%, respectively. However, this was not associated with an improvement of glomerular pathology, interstitial pathology, or of overall survival of Col4a3‐deficient mice. We conclude that Ccl2 mediates the recruitment of glomerular and interstitial macrophages but this mechanism does not contribute to the progression of Alport nephropathy in Col4a3‐deficient mice. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Calcineurin deficiency decreases inflammatory lesions in transforming growth factor β1‐deficient mice

Transforming growth factor (TGF) β1) is an immunoregulatory cytokine involved in self-tolerance and lymphocyte homeostasis. Tgfb1 knock-out (KO) mice develop severe multi-focal autoimmune inflammatory lesions due to [Ca²⁺]i deregulation in T cells, and die within 3 weeks after birth. Because the calcineurin inhibitor FK506 inhibits the hyperresponsiveness of Tgfb1^−/− thymocytes, and because calcineurin Aβ (CNAβ)-deficient mice do not reject allogenic tumours, we have generated Tgfb1^−/−Cnab^−/− mice to address whether CNAβ deficiency prevents T cell activation and inflammation in Tgfb1^−/− mice. Here we show that in Tgfb1^−/−Cnab^−/− mice inflammation is reduced significantly relative to that in Tgfb1^−/− mice. However, both CD4⁺ and CD8⁺ T cells in double knock-out (DKO) mice are activated, as revealed by up-regulation of CD11a lymphocyte function-associated antigen-1 (LFA-1), CD44 and CD69 and down-regulation of CD62L. These data suggest that deficiency of CNAβ decreases inflammatory lesions but does not prevent activation of autoreactive T cells. Also Tgfb1^−/− T cells can undergo activation in the absence of CNAβ, probably by using the other isoform of calcineurin (CNAα) in a compensatory manner. CNAβ-deficient T cells undergo spontaneous activation in vivo and are activated upon anti-T cell receptor stimulation in vitro. Understanding the role of calcineurin in T cell regulation should open up new therapeutic opportunities for inflammation and cancer.     

Sequential testicular atrophy involves changes in cellular proliferation and apoptosis associated with variations in aromatase P450 expression levels in Irs‐2‐deficient mice

Insulin receptor substrate 2 (Irs‐2) is an intracellular protein susceptible to phosphorylation after activation of the insulin receptor. Its suppression affects testis development and its absence induces peripheral resistance to insulin. The aim of this study was to identify changes induced by the deletion of Irs‐2 in the testicular structure and by the altered expression of cytochrome P450 aromatase, a protein necessary for the development and maturation of germ cells. Adult knockout (KO) mice (Irs‐2^?/?, 6 and 12 weeks old) and age‐matched wild‐type (WT) mice were used in this study. Immunohistochemistry and Western blot analyses were performed to study proliferation (PCNA), apoptosis (active caspase‐3) and P450 aromatase expression in testicular histological sections. Deletion of Irs‐2 decreased the number of epithelial cells in the seminiferous tubule and rete testis. Aberrant cells were frequently detected in the epithelia of Irs‐2^?/? mice, accompanied by variations in spermatogonia, which were shown to exhibit small hyperchromatic nuclei as well as polynuclear and anuclear structures. The amount of cell proliferation was significantly lower in Irs‐2^?/? mice than in WT mice, whereas apoptotic processes were more common in Irs‐2^?/? mice. Aromatase P450 reactivity was higher in 6‐week‐old KO mice than in WT mice of the same age and was even higher at 12 weeks. Our results suggest that Irs‐2 is a key element in spermatogenesis because silencing Irs‐2 induces the sequential development of testicular atrophy. The effects are observed mainly in germ cells present in the seminiferous tubule, which may be due to changes in cytochrome P450 aromatase expression.     

促红细胞生成素对急性肾损伤大鼠肾小管细胞凋亡和p-MAPKAPK-2表达的影响

目的:探讨促红细胞生成素(EPO)对急性肾损伤大鼠肾小管细胞凋亡和MAPKAPK-2水平的影响.方法:30只SD雄性大鼠分为假手术组、模型组、EPO治疗组,假手术组仅分离肾被膜后逐层关闭腹腔;模型组采用缺血再灌注法建立急性肾损伤模型;EPO治疗组为急性肾损伤大鼠腹腔注射EPO 50 U/kg,每周3次,共6周,其余大鼠...     

Deficient liver regeneration after carbon tetrachloride injury in mice lacking type 1 but not type 2 tumor necrosis factor receptor.

Signaling by tumor necrosis factor type 1 receptor (TNFR-1) is required for the initiation of liver regeneration after partial hepatectomy. Using knockout mice that lack either TNFR-1 or TNFR-2, we determined whether signaling through TNF receptors is important for liver injury and hepatocyte proliferation induced by carbon tetrachloride (CCl4). Lack of TNFR-1 inhibited hepatocyte DNA synthesis after CCl4 injection. At 44 hours after the injection, replication of hepatocytes in TNFR-1 was 50% to 90% lower than in wild-type (WT) animals, depending on the dose injected. In WT animals, hepatocyte replication was essentially completed by 4 days after CCl4 injection, but replication at a low level persisted in TNFR-1 mice for at least 2 weeks. TNFR-1 knockout mice had little detectable NF-kappa B and STAT3 binding during the first 5 hours after CCl4, high plasma TNF, and reduced levels of plasma interleukin (IL)-6 and liver IL-6 mRNA. Injection of IL-6 30 minutes before CCl4 administration corrected the deficiency of hepatocyte replication at 44 hours and restored STAT3 binding to normal levels. In contrast, mice lacking TNFR-2 did not differ significantly from WT mice in NF-kappa B and STAT3 binding, IL-6 and TNF levels, or hepatocyte replication. Although AP-1 binding was induced in WT TNFR-1 and TNFR-2 knockout mice, binding in TNFR-2 knockouts was lower than in WT mice. C/EBP binding was much lower in TNFR-1 and TNFR-2 knockout mice than in WT mice. As assessed by morphological analysis and alanine aminotransferase levels, the acute injury caused by CCl4 appeared to be similar in the three groups of animals, but subsequent regeneration was impaired in mice lacking TNFR-1. We conclude that a TNFR-1 signaling pathway involving NF-kappa B, IL-6, and STAT3 is an important component of the hepatocyte mitogenic response induced by CCl4 injury in mouse liver.     

BCL‐2 levels do not predict azathioprine treatment response in inflammatory bowel disease,but inhibition induces lymphocyte apoptosis and ameliorates colitis in mice

In inflammatory bowel disease (IBD), inflammation is sustained by an exaggerated response of lymphocytes. This results from enhanced expression of anti‐apoptotic B cell lymphoma (BCL‐2) and BCL‐XL associated with a diminished turnover. Azathioprine (AZA) directly targets BCL‐2 family‐mediated apoptosis. We investigated whether the BCL‐2 family expression pattern could be used to predict treatment response to AZA and determined whether BCL‐2 inhibitor A‐1211212 effectively diminishes lymphocytes and ameliorates inflammation in a model of colitis. BCL‐2 family expression pattern was determined by next‐generation sequencing (NGS). BCL‐2 inhibitor was administered orally to Il10‐/‐ mice. Haematological analyses were performed with an ADVIA 2120 and changes in immune cells were investigated using quantitative polymerase chain reaction (qPCR) and fluorescence activated cell sorter (FACS). We determined similar expression levels of BCL‐2 family members in patients with remission and patients refractory to treatment, showing that BCL‐2 family expression can not predict AZA treatment response. Expression was not correlated with the modified Truelove and Witts activity index (MTWAI). BCL‐2 inhibitor initiated cell death in T cells from patients refractory to AZA and reduced lymphocyte count in Il10‐/‐ mice. FACS revealed diminished CD8⁺ T cells upon BCL‐2 inhibitor in Il10‐/‐ mice without influencing platelets. Tnf, Il1β, Ifn? and Mcp‐1 were decreased upon BCL‐2 inhibitor. A‐1211212 positively altered the colonic mucosa and ameliorated inflammation in mice. Pro‐apoptotic BCL‐2 inhibitor A‐1211212 diminishes lymphocytes and ameliorates colitis in Il10‐/‐ mice without inducing thrombocytopenia. BCL‐2 inhibition could be a new therapy option for patients refractory to AZA.     

Lack of adrenomedullin,but not complement factor H,results in larger infarct size and more extensive brain damage in a focal ischemia model

Adrenomedullin (AM) and its binding protein, complement factor H (FH), are expressed throughout the brain. In this study we used a brain-specific conditional knockout for AM and a complete knockout for FH to investigate the effect of these molecules on the pathophysiology of stroke. Following 48 h of middle cerebral artery permanent occlusion, there was a statistically significant infarct size increase in animals lacking AM when compared to their wild type littermates. In contrast, lack of FH did not affect infarct volume. To investigate some of the mechanisms by which lack of AM may augment brain damage, markers of nitrosative stress, apoptosis, and autophagy were studied at the mRNA and protein levels. There was a significant increase of inducible nitric oxide synthase (iNOS), matrix metalloproteinase-9 (MMP9), fractin, and Beclin-1 in the peri-infarct area of AM-deficient mice when compared to their wild type counterparts and to contralateral and sham-operated controls. These data suggest that AM exerts a neuroprotective action in the brain and that this protection may be mediated by regulation of iNOS, matrix metalloproteases, and inflammatory mediators. In the future, substances that increase AM actions in the central nervous system may be used as potential neuroprotective agents in stroke.     

Impaired removal of Vβ8+ lymphocytes aggravates colitis in mice deficient for B cell lymphoma‐2‐interacting mediator of cell death (Bim)

We investigated the role of B cell lymphoma (BCL)‐2‐interacting mediator of cell death (Bim) for lymphocyte homeostasis in intestinal mucosa. Lymphocytes lacking Bim are refractory to apoptosis. Chronic colitis was induced in Bim‐deficient mice (Bim^–/–) with dextran sulphate sodium (DSS). Weight loss and colonoscopic score were increased significantly in Bim^–/– mice compared to wild‐type mice. As Bim is induced for the killing of autoreactive cells we determined the role of Bim in the regulation of lymphocyte survival at mucosal sites. Upon chronic dextran sulphate sodium (DSS)‐induced colitis, Bim^–/– animals exhibited an increased infiltrate of lymphocytes into the mucosa compared to wild‐type mice. The number of autoreactive T cell receptor (TCR) Vβ8⁺ lymphocytes was significantly higher in Bim^–/– mice compared to wild‐type controls. Impaired removal of autoreactive lymphocytes in Bim^–/– mice upon chronic DSS‐induced colitis may therefore contribute to aggravated mucosal inflammation.     

Skin wound healing in diabetic β6 integrin‐deficient mice

Jacobsen JN, Steffensen B, Häkkinen L, Krogfelt KA, Larjava HS. Skin wound healing in diabetic β6 integrin‐deficient mice. APMIS 2010; 118: 753–64. Integrin αvβ6 is a heterodimeric cell surface receptor, which is absent from the normal epithelium, but is expressed in wound‐edge keratinocytes during re‐epithelialization. However, the function of the αvβ6 integrin in wound repair remains unclear. Impaired wound healing in patients with diabetes constitutes a major clinical problem worldwide and has been associated with the accumulation of advanced glycated endproducts (AGEs) in the tissues. AGEs may account for aberrant interactions between integrin receptors and their extracellular matrix ligands such as fibronectin (FN). In this study, we compared healing of experimental excisional skin wounds in wild‐type (WT) and β6‐knockout (β6^?/?) mice with streptozotocin‐induced diabetes. Results showed that diabetic β6^?/? mice had a significant delay in early wound closure rate compared with diabetic WT mice, suggesting that αvβ6 integrin may serve as a protective role in re‐epithelialization of diabetic wounds. To mimic the glycosylated wound matrix, we generated a methylglyoxal (MG)‐glycated variant of FN. Keratinocytes utilized αvβ6 and β1 integrins for spreading on both non‐glycated and FN‐MG, but their spreading was reduced on FN‐MG. These findings indicated that glycation of FN and possibly other integrin ligands could hamper keratinocyte interactions with the provisional matrix proteins during re‐epithelialization of diabetic wounds.     

Interleukin‐37 ameliorates myocardial ischaemia/reperfusion injury in mice

Innate immune and inflammatory responses are involved in myocardial ischaemia/reperfusion (I/R) injury. Interleukin (IL)‐37 is a newly identified member of the IL‐1 family, and functions as a fundamental inhibitor of innate immunity and inflammation. However, its role in myocardial I/R injury remains unknown. I/R or sham operations were performed on male C57BL/6J mice. I/R mice received an injection of recombinant human IL‐37 or vehicle, immediately before reperfusion. Compared with vehicle treatment, mice treated with IL‐37 showed an obvious amelioration of the I/R injury, as demonstrated by reduced infarct size, decreased cardiac troponin T level and improved cardiac function. This protective effect was associated with the ability of IL‐37 to suppress production of proinflammatory cytokines, chemokines and neutrophil infiltration, which together contributed to a decrease in cardiomyocyte apoptosis and reactive oxygen species (ROS) generation. In addition, we found that IL‐37 inhibited the up‐regulation of Toll‐like receptor (TLR)‐4 expression and nuclear factor kappa B (NF‐kB) activation after I/R, while increasing the anti‐inflammatory IL‐10 level. Moreover, the administration of anti‐IL‐10R antibody abolished the protective effects of IL‐37 in I/R injury. In‐vitro experiments further demonstrated that IL‐37 protected cardiomyocytes from apoptosis under I/R condition, and suppressed the migration ability of neutrophils towards the chemokine LIX. In conclusion, IL‐37 plays a protective role against mouse myocardial I/R injury, offering a promising therapeutic medium for myocardial I/R injury.