Lung Natural Killer Cells Play a Major Counter-Regulatory Role in Pulmonary Vascular Hyperpermeability After Myocardial Infarction

Abstract

Rationale: Natural killer (NK) cells are lymphocytes of the innate immune system that play specialized and nichespecific roles in distinct organs. Objective:We investigated the possible function of NK cells in the pathogenesis of congestive heart failure after myocardial infarction. Methods and Results: Depletion of NK cells from mice had little effect on cytokine expression (tumor necrosisfactor-α, interleukin [IL]-6, and IL-1β), neutrophil and macrophage infiltration into infarcted myocardium, or left ventricular remodeling after myocardial infarction. However, these mice exhibited severe respiratory distress associated with protein-rich, high-permeability alveolar edema accompanied by neutrophil infiltration. In addition, there were 20-fold more NK cells in the mouse lungs than in heart, and these cells were accumulated around the vasculature. CD107a-positive and interferon-γ-positive cell populations were unchanged, whereas IL-10-positive populations increased. Adoptive transfer of NK cells from wild-type mice, but not from IL-10 knockout mice, into the NK cell-depleted mice rescued the respiratory phenotype. IL-1β-mediated dextran leakage from a lung endothelial cell monolayer was also blocked by coculture with NK cells from wild-type mice but not from IL-10 knockout mice. by respective effector functions. NK cells are cytotoxic lymphocytes critical to the innate immune system that can differentiate and mature in the bone marrow, lymph node, spleen, tonsils, and thymus before entering the circulation. In contrast to NKT cells, NK cells do not express invariant T-cell antigen receptors, Pan T marker CD3, or surface immunoglobulin (Ig) B cell receptors, but they usually express the surface markers CD16 (FcγRIII) and CD56 in humans, and NK1.1 in mice. NK cells play a highly important role in the killing of tumors and cells infected by viruses, and can have specialized and niche-specific functions in distinct organs. Conclusions:In the present study, we sought to examine the roles of cardiac NK cells in the pathogenesis of LV remodeling after MI. Unexpectedly, depletion of NK cells from mice had little effect on LV remodeling after MI; however, these mice exhibited severe respiratory distress associated with protein-rich, high-permeability alveolar edema accompanied by neutrophil infiltration. Thus, we examined a mechanism for lung NK cells in protecting lung from the development of cardiogenic pulmonary edema after MI. MethodsAn expanded Materials and Methods section is available in the online Data Supplement. Results Genetic Ablation of NK Cells Exacerbated Cardiogenic Pulmonary Edema After MIWe used a mouse model of nonreperfused MI to examine the possible role of NK cells in the pathogenesis of cardiac remodeling after MI. A detailed temporal analysis of cellular infiltrate dynamics in the post-MI heart revealed an initial increase in the number of NK cells on day 3 after MI, to a peak on day 7 (Online Figure I). In this study, we took advantage of the NKDTR/EGFP transgenic mice that express enhanced green ...

Wogonin inhibits LPS-induced vascular permeability via suppressing MLCK/MLC pathway

“…Vascular hyperpermeability is a common pathogenic process which is often found during the development of several malignant diseases such as diabetic retinopathy [53], solid tumors [35], myocardial infarction [54], wounds [15], and chronic inflammation [28]. The determining structure of vascular permeability [34] is endothelial integrity, which is tightly controlled by many types of signals such as physiological factors (VEGF, TNF or INFγ), oxidative stress and pro-inflammatory cytokines [1,20].…”

Local Microenvironment Controls the Compartmentalization of NK Cell Responses during Systemic Inflammation in Mice

“…Although a clear role for inflammatory IFN-g-producing NKs is established in systemic inflammation (11,12), defining a role for IL-10-producing NKs requires more experimental evidence. However, it is possible that NK-derived IL-10 plays a regulatory role in preventing further damage to the organism, as was shown in the case of myocardial infarction (39).…”

miR‐34b‐5p inhibition attenuates lung inflammation and apoptosis in an LPS‐induced acute lung injury mouse model by targeting progranulin

“…Neutrophils are recruited to the alveolar space and lung interstitium, thereby producing large quantities of chemokines, such as chemokines KC (CXCL‐1) and MIP‐2 (CXCL‐2) (Lerner, Lei, Sundar, & Rahman, ; Rancan et al, ), and reactive oxygen species (ROS) (Spassov et al, ), and neutrophils play critical roles in the development of ALI. Alveolar macrophages also play important roles in the release many pro‐inflammatory cytokines, such as IL‐1β, TNF‐α, and IL‐6 (Parpaleix et al, ; Yan et al, ). In this study, the functional analysis demonstrated that both Ad‐PGRN and Ad‐PGRN‐shRNA caused significant changes in PGRN expression in vivo and that these changes were sustained for a long time.…”