CD69 controls the uptake of L-tryptophan through LAT1-CD98 and AhR-dependent secretion of IL-22 in psoriasis.

The activation marker CD69 is expressed by skin γδ T cells. Here we found that CD69 controlled the aryl hydrocarbon receptor (AhR)-dependent secretion of interleukin 22 (IL-22) by γδ T cells, which contributed to the development of psoriasis induced by IL-23. CD69 associated with the aromatic-amino-acid-transporter complex LAT1-CD98 and regulated its surface expression and uptake of L-tryptophan (L-Trp) and the intracellular quantity of L-Trp-derived activators of AhR. In vivo administration of L-Trp, an inhibitor of AhR or IL-22 abrogated the differences between CD69-deficient mice and wild-type mice in skin inflammation. We also observed LAT1-mediated regulation of AhR activation and IL-22 secretion in circulating Vγ9(+) γδ T cells of psoriatic patients. Thus, CD69 serves as a key mediator of the pathogenesis of psoriasis by controlling LAT1-CD98-mediated metabolic cues.

MICa/b-dependent activation of natural killer cells by CD64+ inflammatory type 2 dendritic cells contributes to autoimmunity.

Primary Sjögren's syndrome (pSS) is an inflammatory autoimmune disorder largely mediated by type I and II interferon (IFN). The potential contribution of innate immune cells, such as natural killer (NK) cells and dendritic cells (DC), to the pSS pathology remains understudied. Here, we identified an enriched CD16+ CD56hi NK cell subset associated with higher cytotoxic function, as well as elevated proportions of inflammatory CD64+ conventional dendritic cell (cDC2) subtype that expresses increased levels of MICa/b, the ligand for the activating receptor NKG2D, in pSS individuals. Circulating cDC2 from pSS patients efficiently induced activation of cytotoxic NK cells ex vivo and were found in proximity to CD56+ NK cells in salivary glands (SG) from pSS patients. Interestingly, transcriptional activation of IFN signatures associated with the RIG-I/DDX60 pathway, IFN I receptor, and its target genes regulate the expression of NKG2D ligands on cDC2 from pSS patients. Finally, increased proportions of CD64hi RAE-1+ cDC2 and NKG2D+ CD11b+ CD27+ NK cells were present in vivo in the SG after poly I:C injection. Our study provides novel insight into the contribution and interplay of NK and cDC2 in pSS pathology and identifies new potential therapy targets.

Imbalance of SARS-CoV-2-specific CCR6+ and CXCR3+ CD4+ T cells and IFN-γ + CD8+ T cells in patients with Long-COVID.

Long-COVID (LC) is characterised by persistent symptoms for at least 3 months after acute infection. A dysregulation of the immune system and a persistent hyperinflammatory state may cause LC. LC patients present differences in activation and exhaustion states of innate and adaptive compartments. Different T CD4+ cell subsets can be identified by differential expression of chemokine receptors (CCR). However, changes in T cells with expression of CCRs such as CCR6 and CXCR3 and their relationship with CD8+ T cells remains unexplored in LC. Here, we performed unsupervised analysis and found CCR6+ CD4+ subpopulations enriched in COVID-19 convalescent individuals upon activation with SARS-CoV-2 peptides. SARS-CoV-2 specific CCR6+ CD4+ are decreased in LC patients, whereas CXCR3+ CCR6- and CCR4+ CCR6- CD4+ T cells are increased. LC patients showed lower IFN-γ-secreting CD8+ T cells after stimulation with SARS-CoV-2 Spike protein. This work underscores the role of CCR6 in the pathophysiology of LC.

A Novel Circulating MicroRNA for the Detection of Acute Myocarditis.

BACKGROUND: The diagnosis of acute myocarditis typically requires either endomyocardial biopsy (which is invasive) or cardiovascular magnetic resonance imaging (which is not universally available). Additional approaches to diagnosis are desirable. We sought to identify a novel microRNA for the diagnosis of acute myocarditis. METHODS: To identify a microRNA specific for myocarditis, we performed microRNA microarray analyses and quantitative polymerase-chain-reaction (qPCR) assays in sorted CD4+ T cells and type 17 helper T (Th17) cells after inducing experimental autoimmune myocarditis or myocardial infarction in mice. We also performed qPCR in samples from coxsackievirus-induced myocarditis in mice. We then identified the human homologue for this microRNA and compared its expression in plasma obtained from patients with acute myocarditis with the expression in various controls. RESULTS: We confirmed that Th17 cells, which are characterized by the production of interleukin-17, are a characteristic feature of myocardial injury in the acute phase of myocarditis. The microRNA mmu-miR-721 was synthesized by Th17 cells and was present in the plasma of mice with acute autoimmune or viral myocarditis but not in those with acute myocardial infarction. The human homologue, designated hsa-miR-Chr8:96, was identified in four independent cohorts of patients with myocarditis. The area under the receiver-operating-characteristic curve for this novel microRNA for distinguishing patients with acute myocarditis from those with myocardial infarction was 0.927 (95% confidence interval, 0.879 to 0.975). The microRNA retained its diagnostic value in models after adjustment for age, sex, ejection fraction, and serum troponin level. CONCLUSIONS: After identifying a novel microRNA in mice and humans with myocarditis, we found that the human homologue (hsa-miR-Chr8:96) could be used to distinguish patients with myocarditis from those with myocardial infarction. (Funded by the Spanish Ministry of Science and Innovation and others.).

CD69-oxLDL ligand engagement induces Programmed Cell Death 1 (PD-1) expression in human CD4 + T lymphocytes.

The mechanisms that control the inflammatory-immune response play a key role in tissue remodelling in cardiovascular diseases. T cell activation receptor CD69 binds to oxidized low-density lipoprotein (oxLDL), inducing the expression of anti-inflammatory NR4A nuclear receptors and modulating inflammation in atherosclerosis. To understand the downstream T cell responses triggered by the CD69-oxLDL binding, we incubated CD69-expressing Jurkat T cells with oxLDL. RNA sequencing revealed a differential gene expression profile dependent on the presence of CD69 and the degree of LDL oxidation. CD69-oxLDL binding induced the expression of NR4A receptors (NR4A1 and NR4A3), but also of PD-1. These results were confirmed using oxLDL and a monoclonal antibody against CD69 in CD69-expressing Jurkat and primary CD4 + lymphocytes. CD69-mediated induction of PD-1 and NR4A3 was dependent on NFAT activation. Silencing NR4A3 slightly increased PD-1 levels, suggesting a potential regulation of PD-1 by this receptor. Moreover, expression of PD-1, CD69 and NR4A3 was increased in human arteries with chronic inflammation compared to healthy controls, with a strong correlation between PD-1 and CD69 mRNA expression (r = 0.655 P < 0.0001). Moreover, PD-1 was expressed in areas enriched in CD3 infiltrating T cells. Our results underscore a novel mechanism of PD-1 induction independent of TCR signalling that might contribute to the role of CD69 in the modulation of inflammation and vascular remodelling in cardiovascular diseases.

Deregulated cellular circuits driving immunoglobulins and complement consumption associate with the severity of COVID-19 patients.

SARS-CoV-2 infection causes an abrupt response by the host immune system, which is largely responsible for the outcome of COVID-19. We investigated whether the specific immune responses in the peripheral blood of 276 patients were associated with the severity and progression of COVID-19. At admission, dramatic lymphopenia of T, B, and NK cells is associated with severity. Conversely, the proportion of B cells, plasmablasts, circulating follicular helper T cells (cTfh) and CD56- CD16+ NK-cells increased. Regarding humoral immunity, levels of IgM, IgA, and IgG were unaffected, but when degrees of severity were considered, IgG was lower in severe patients. Compared to healthy donors, complement C3 and C4 protein levels were higher in mild and moderate, but not in severe patients, while the activation peptide of C5 (C5a) increased from the admission in every patient, regardless of their severity. Moreover, total IgG, the IgG1 and IgG3 isotypes, and C4 decreased from day 0 to day 10 in patients who were hospitalized for more than two weeks, but not in patients who were discharged earlier. Our study provides important clues to understand the immune response observed in COVID-19 patients, associating severity with an imbalanced humoral response, and identifying new targets for therapeutic intervention.

The impact of type 2 immunity and allergic diseases in atherosclerosis.

Allergic diseases are allergen-induced immunological disorders characterized by the development of type 2 immunity and IgE responses. The prevalence of allergic diseases has been on the rise alike cardiovascular disease (CVD), which affects arteries of different organs such as the heart, the kidney and the brain. The underlying cause of CVD is often atherosclerosis, a disease distinguished by endothelial dysfunction, fibrofatty material accumulation in the intima of the artery wall, smooth muscle cell proliferation, and Th1 inflammation. The opposed T-cell identity of allergy and atherosclerosis implies an atheroprotective role for Th2 cells by counteracting Th1 responses. Yet, the clinical association between allergic disease and CVD argues against it. Within, we review different phases of allergic pathology, basic immunological mechanisms of atherosclerosis and the clinical association between allergic diseases (particularly asthma, atopic dermatitis, allergic rhinitis and food allergy) and CVD. Then, we discuss putative atherogenic mechanisms of type 2 immunity and allergic inflammation including acute allergic reactions (IgE, IgG1, mast cells, macrophages and allergic mediators such as vasoactive components, growth factors and those derived from the complement, contact and coagulation systems) and late phase inflammation (Th2 cells, eosinophils, type 2 innate-like lymphoid cells, alarmins, IL-4, IL-5, IL-9, IL-13 and IL-17).

The double injection technique to improve visualization of severe coronary lesions with optical coherence tomography.

BACKGROUND: Optical coherence tomography (OCT) is a high-resolution imaging modality that provides a precise evaluation of coronary anatomy. However, the presence of severe coronary lesions can prevent the required adequate distal contrast flushing resultting in inadequate blood clearance and poor image quality or complete blood shadowing of the underlying vessel wall. OBJECTIVES: The aim of this prospective study was to evaluate the feasibility and safety of a novel "double injection technique" (DIT) to overcome the limitations of the conventional technique (CT) in patients with severely stenotic lesions. METHODS: Twenty-three patients with severe angiographic lesions were sequentially imaged before intervention with OCT with the CT and then with DIT. A total of 5125 OCT frames were carefully matched and analyzed by an independent central core lab. A semiquantitative image quality score was used to grade the number of quadrants (0-4) with vessel wall visualization. RESULTS: Optimal OCT visualization (Grades 3-4) significantly improved by the DIT (68% vs. 38% of frames, p < 0.001). The DIT also improved the mean score (3.1 ± 0.6 vs. 2.0 ± 0.8; p < 0.05; mean improvement of 1.1 ± 0.5 per patient). There were no complications associated with the DIT. CONCLUSION: The DIT significantly improved preintervention image quality of OCT in severe coronary lesions.

Genetic LGALS1 Variants Are Associated with Heterogeneity in Galectin-1 Serum Levels in Patients with Early Arthritis.

Galectin 1 (Gal1) exerts immunomodulatory effects leading to therapeutic effects in autoimmune animal models. Patients with rheumatoid arthritis have been reported to show higher Gal1 serum levels than the healthy population. Our study aimed to find genetic variants on the Gal1 gene (LGALS1) modulating its expression and/or clinical features in patients with early arthritis (EA). LGALS1 was sequenced in 53 EA patients to characterize all genetic variants. Then, we genotyped rs9622682, rs929039, and rs4820293, which covered the main genetic variation in LGALS1, in 532 EA patients. Gal1 and IL-6 serum levels were measured by ELISA and Gal1 also by western blot (WB) in lymphocytes from patients with specific genotypes. Once disease activity improved with treatment, patients with at least one copy of the minor allele in rs9622682 and rs929039 or those with GG genotype in rs4820293 showed significantly higher Gal1 serum levels (p < 0.05). These genotypic combinations were also associated with higher Gal1 expression in lymphocytes by WB and lower IL-6 serum levels in EA patients. In summary, our study suggests that genetic variants studied in LGALS1 can explain heterogeneity in Gal1 serum levels showing that patients with higher Gal1 levels have lower serum IL-6 levels.

VIP/VPAC Axis Expression in Immune-Mediated Inflammatory Disorders: Associated miRNA Signatures.

Few studies have considered immune-mediated inflammatory disorders (IMID) together, which is necessary to adequately understand them given they share common mechanisms. Our goal was to investigate the expression of vasoactive intestinal peptide (VIP) and its receptors VPAC1 and VPAC2 in selected IMID, analyze the effect of biological therapies on them, and identify miRNA signatures associated with their expression. Serum VIP levels and mRNA of VPAC and miRNA expression in peripheral blood mononuclear cells were analyzed from 52 patients with psoriasis, rheumatoid arthritis, Graves' disease, or spondyloarthritis and from 38 healthy subjects. IMID patients showed higher levels of VIP and increased expression of VPAC2 compared to controls (p < 0.0001 and p < 0.0192, respectively). Receiver operating characteristic curve analysis showed that the levels of VIP or VPAC2 expression were adequate discriminators capable of identifying IMID. Treatment of IMID patients with anti-TNFα and anti-IL12/23 significantly affected serum VIP levels. We identified miRNA signatures associated with levels of serum VIP and VPAC2 expression, which correlated with IMID diagnosis of the patients. The results indicate that the expression of VIP/VPAC2 is able of identify IMIDs and open up a line of research based on the association between the VIP/VPAC axis and miRNA signatures in immune-mediated diseases.

Targeting L-type amino acid transporter 1 in innate and adaptive T cells efficiently controls skin inflammation.

BACKGROUND: Psoriasis is a frequent inflammatory skin disease that is mainly mediated by IL-23, IL-1ß, and IL-17 cytokines. Although psoriasis is a hyperproliferative skin disorder, the possible role of amino acid transporters has remained unexplored. OBJECTIVE: We sought to investigate the role of the essential amino acid transporter L-type amino acid transporter (LAT) 1 (SLC7A5) in psoriasis. METHODS: LAT1 floxed mice were crossed to Cre-expressing mouse strains under the control of keratin 5, CD4, and retinoic acid receptor-related orphan receptor γ. We produced models of skin inflammation induced by imiquimod (IMQ) and IL-23 and tested the effect of inhibiting LAT1 (JPH203) and mammalian target of rapamycin (mTOR [rapamycin]). RESULTS: LAT1 expression is increased in keratinocytes and skin-infiltrating lymphocytes of psoriatic lesions in human subjects and mice. LAT1 deletion in keratinocytes does not dampen the inflammatory response or their proliferation, which could be maintained by increased expression of the alternative amino acid transporters LAT2 and LAT3. Specific deletion of LAT1 in γδ and CD4 T cells controls the inflammatory response induced by IMQ. LAT1 deletion or inhibition blocks expansion of IL-17-secreting γ4+δ4+ and CD4 T cells and dampens the release of IL-1ß, IL-17, and IL-22 in the IMQ-induced model. Moreover, inhibition of LAT1 blocks expansion of human γδ T cells and IL-17 secretion by human CD4 T cells. IL-23 and IL-1ß stimulation upregulates LAT1 expression and induces mTOR activation in IL-17+ γδ and TH17 cells. Deletion or inhibition of LAT1 efficiently controls IL-23- and IL-1ß-induced phosphatidylinositol 3-kinase/AKT/mTOR activation independent of T-cell receptor signaling. CONCLUSION: Targeting LAT1-mediated amino acid uptake is a potentially useful immunosuppressive strategy to control skin inflammation mediated by the IL-23/IL-1ß/IL-17 axis.

Oxidized Low-Density Lipoprotein Receptor in Lymphocytes Prevents Atherosclerosis and Predicts Subclinical Disease.

BACKGROUND: Although the role of Th17 and regulatory T cells in the progression of atherosclerosis has been highlighted in recent years, their molecular mediators remain elusive. We aimed to evaluate the association between the CD69 receptor, a regulator of Th17/regulatory T cell immunity, and atherosclerosis development in animal models and in patients with subclinical disease. METHODS: Low-density lipoprotein receptor-deficient chimeric mice expressing or not expressing CD69 on either myeloid or lymphoid cells were subjected to a high fat diet. In vitro functional assays with human T cells were performed to decipher the mechanism of the observed phenotypes. Expression of CD69 and NR4A nuclear receptors was evaluated by reverse transcription-polymerase chain reaction in 305 male participants of the PESA study (Progression of Early Subclinical Atherosclerosis) with extensive (n=128) or focal (n=55) subclinical atherosclerosis and without disease (n=122). RESULTS: After a high fat diet, mice lacking CD69 on lymphoid cells developed large atheroma plaque along with an increased Th17/regulatory T cell ratio in blood. Oxidized low-density lipoprotein was shown to bind specifically and functionally to CD69 on human T lymphocytes, inhibiting the development of Th17 cells through the activation of NR4A nuclear receptors. Participants of the PESA study with evidence of subclinical atherosclerosis displayed a significant CD69 and NR4A1 mRNA downregulation in peripheral blood leukocytes compared with participants without disease. The expression of CD69 remained associated with the risk of subclinical atherosclerosis in an adjusted multivariable logistic regression model (odds ratio, 0.62; 95% CI, 0.40-0.94; P=0.006) after adjustment for traditional risk factors, the expression of NR4A1, the level of oxidized low-density lipoprotein, and the counts of different leucocyte subsets. CONCLUSIONS: CD69 depletion from the lymphoid compartment promotes a Th17/regulatory T cell imbalance and exacerbates the development of atherosclerosis. CD69 binding to oxidized low-density lipoprotein on T cells induces the expression of anti-inflammatory transcription factors. Data from a cohort of the PESA study with subclinical atherosclerosis indicate that CD69 expression in PBLs inversely correlates with the presence of disease. The expression of CD69 remained an independent predictor of subclinical atherosclerosis after adjustment for traditional risk factors.

Immunomodulatory role of microRNAs transferred by extracellular vesicles.

The immune system is composed of different cell types localised throughout the organism to sense and respond to pathological situations while maintaining homeostasis under physiological conditions. Intercellular communication between immune cells is essential to coordinate an effective immune response and involves both cell contact dependent and independent processes that ensure the transfer of information between bystander and distant cells. There is a rapidly growing body of evidence on the pivotal role of extracellular vesicles (EVs) in cell communication and these structures are emerging as important mediators for immune modulation upon delivery of their molecular cargo. In the last decade, EVs have been shown to be efficient carriers of genetic information, including microRNAs (miRNAs), that can be transferred between cells and regulate gene expression and function on the recipient cell. Here, we review the current knowledge of intercellular functional transfer of EV-delivered miRNAs and their putative role in immune regulation.

The incidence of cardiovascular events after hospitalization due to CAP and their association with different inflammatory markers.

BACKGROUND: Late prognosis of Community-Acquired Pneumonia (CAP) patients is related to cardiovascular events. Persistence of inflammation-related markers, defined by high circulatory levels of interleukin 6 and 10 (IL-6/IL-10), is associated with a higher post-event mortality rate for CAP patients. However, association between these markers and other components of the immune response, and the risk of cardiovascular events, has not been adequately explored. The main objectives of this study are: 1) to quantify the incidence of cardiovascular disease, in the year post-dating their hospital admittance due to CAP and, 2) to describe the distribution patterns of a wide spectrum of inflammatory markers upon admittance to and release from hospital, and to determine their relationship with the incidence of cardiovascular disease. METHODS/DESIGN: A cohort prospective study. All patients diagnosed and hospitalized with CAP will be candidates for inclusion. The study will take place in the Universitary Hospital La Princesa, Spain, during two years. Two samples of blood will be taken from each patient: the first upon admittance and the second one prior to release, in order to analyse various immune agents. The main determinants are: pro-adrenomedullin, copeptin, IL-1, IL-6, TNF-α, IL-17, IFN-γ, IL-10 and TGF-ß, E-Selectin, ICAM-1, VCAM-1 and subpopulations of peripheral T lymphocytes (T regulator, Th1 and Th17), together with other clinical and analytical variables. Follow up will start at admittance and finish a year after discharge, registering incidence of death and cardiovascular events. The main objective is to establish the predictive power of different inflammatory markers in the prognosis of CAP, in the short and long term, and their relationship with cardiovascular disease. DISCUSSION: The level of some inflammatory markers (IL-6/IL-10) has been proposed as a means to differentiate the degree of severity of CAP, but their association with cardiovascular risk is not well established. In this study we aim to define new inflammatory markers associated with cardiovascular disease that could be helpful for the prognosis of CAP patients, by describing the distribution of a wide spectrum of inflammatory mediators and analyzing their association with the incidence of cardiovascular disease and mortality one year after release from hospital.

Beneficial effect of temporary methotrexate interruption on B and T cell responses upon SARS-CoV-2 vaccination in patients with rheumatoid arthritis or psoriatic arthritis.

B and T cell responses were evaluated in patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) after 1 or 2 weeks of methotrexate (MTX) withdrawal following each COVID-19 vaccine dose and compared with those who maintained MTX. Adult RA and PsA patients treated with MTX were recruited and randomly assigned to 3 groups: MTX-maintenance (n = 72), MTX-withdrawal for 1 week (n = 71) or MTX-withdrawal for 2 weeks (n = 73). Specific antibodies to several SARS-CoV-2 antigens and interferon (IFN)-γ and interleukin (IL)-21 responses were assessed. MTX withdrawal in patients without previous COVID-19 was associated with higher levels of anti-RBD IgG and neutralising antibodies, especially in the 2-week withdrawal group and with higher IFN-γ secretion upon stimulation with pools of SARS-CoV-2 S peptides. No increment of RA/PsA relapses was detected across groups. Our data indicate that two-week MTX interruption following COVID-19 vaccination in patients with RA or PsA improves humoral and cellular immune responses.

Endosomal clathrin drives actin accumulation at the immunological synapse.

Antigen-specific cognate interaction of T lymphocytes with antigen-presenting cells (APCs) drives major morphological and functional changes in T cells, including actin rearrangements at the immune synapse (IS) formed at the cell-cell contact area. Here we show, using cell lines as well as primary cells, that clathrin, a protein involved in endocytic processes, drives actin accumulation at the IS. Clathrin is recruited towards the IS with parallel kinetics to that of actin. Knockdown of clathrin prevents accumulation of actin and proteins involved in actin polymerization, such as dynamin-2, the Arp2/3 complex and CD2AP at the IS. The clathrin pool involved in actin accumulation at the IS is linked to multivesicular bodies that polarize to the cell-cell contact zone, but not to plasma membrane or Golgi complex. These data underscore the role of clathrin as a platform for the recruitment of proteins that promote actin polymerization at the interface of T cells and APCs.

Unraveling CD69 signaling pathways, ligands and laterally associated molecules.

CD69 is an early leukocyte activation marker involved in the regulation of the immune response. Initial in vitro studies evaluated its function using monoclonal antibodies until knock-out mice were developed. Subsequently, four ligands for CD69 have been identified, namely galectin-1, S100A8/S100A9 complex, myosin light chains 9 and 12, and oxidized low-density lipoproteins. In addition, several molecules are laterally associated with and regulated by CD69, including calreticulin and two transmembrane receptors, sphingosine-1-phosphate receptor (S1P1) and the heterodimeric amino acid transporter complex SLC7A5-SLC3A2 (LAT1-CD98). Recently, CD69 engagement has been shown to induce the expression of the immunoregulatory receptor programmed cell death-1 (PD-1) in T cells. The molecular signaling induced by CD69 has been explored in different scenarios and cell types. This review provides a perspective on the molecular pathways, ligands and cellular functions known to be regulated by CD69.

A Comprehensive Analysis of Immune Response in Patients with Non-Muscle-Invasive Bladder Cancer.

BACKGROUND: Bladder carcinoma has elevated morbimortality due to its high recurrence and progression in localized disease. A better understanding of the role of the tumor microenvironment in carcinogenesis and response to treatment is needed. METHODS: Peripheral blood and samples of urothelial bladder cancer and adjacent healthy urothelial tissue were collected from 41 patients and stratified in low- and high-grade urothelial bladder cancer, excluding muscular infiltration or carcinoma in situ. Mononuclear cells were isolated and labeled for flow cytometry analysis with antibodies aimed at identifying specific subpopulations within T lymphocytes, myeloid cells and NK cells. RESULTS: In peripheral blood and tumor samples, we detected different percentages of CD4+ and CD8+ lymphocytes, monocyte and myeloid-derived suppressor cells, as well as differential expression of activation- and exhaustion-related markers. Conversely, only a significant increase in bladder total monocytes was found when comparing bladder and tumor samples. Interestingly, we identified specific markers differentially expressed in the peripheral blood of patients with different outcomes. CONCLUSION: The analysis of host immune response in patients with NMIBC may help to identify specific markers that allow optimizing therapy and patient follow-up. Further investigation is needed to establish a strong predictive model.

Influence of air pollutants on circulating inflammatory cells and microRNA expression in acute myocardial infarction.

Air pollutants increase the risk and mortality of myocardial infarction (MI). The aim of this study was to assess the inflammatory changes in circulating immune cells and microRNAs in MIs related to short-term exposure to air pollutants. We studied 192 patients with acute coronary syndromes and 57 controls with stable angina. For each patient, air pollution exposure in the 24-h before admission, was collected. All patients underwent systematic circulating inflammatory cell analyses. According to PM2.5 exposure, 31 patients were selected for microRNA analyses. STEMI patients exposed to PM2.5 showed a reduction of CD4+ regulatory T cells. Furthermore, in STEMI patients the exposure to PM2.5 was associated with an increase of miR-146a-5p and miR-423-3p. In STEMI and NSTEMI patients PM2.5 exposure was associated with an increase of miR-let-7f-5p. STEMI related to PM2.5 short-term exposure is associated with changes involving regulatory T cells, miR-146a-5p and miR-423-3p.