Regulatory macrophages and the host inflammatory response

描述(由申请者提供)：本申请旨在研究我们已确认具有强大免疫调节活性的活化巨噬细胞亚群。我们将确定是否可以利用这些调节性巨噬细胞(R-MF)来开发一类新的抗炎疗法。在目标1中，我们将确定调节性巨噬细胞的特征，并确定一组R-MF特异的生物标记物，以开发这些细胞的“签名”。这些生物标记物将被用来确定可以产生调节性巨噬细胞的各种“重新编程”信号，它们将使在疾病期间识别组织中的这些细胞成为可能。我们认为，耗尽或诱导R-MF代表了治疗疾病的新途径。在目标2中，我们将研究经典激活的巨噬细胞(Ca-MF)向调节性巨噬细胞的转化。我们认为，Ca-MF可以通过分泌ATP并将其快速转化为腺苷来控制自己的激活状态。腺苷诱导一种调节性巨噬细胞表型。在没有这种转换的情况下，巨噬细胞的激活不受控制地进行，导致炎症病理。这代表了(控制)巨噬细胞激活的新范式。我们将确定巨噬细胞胞外酶CD39和CD73通过使巨噬细胞过表达或缺失这些胞外酶来促进ATP转化为腺苷的作用。在AIM 1中开发的生物标记物将帮助我们识别腺苷暴露后对调节性巨噬细胞的诱导。在目标3中，我们将操纵巨噬细胞来改善人类健康。我们将诱导R-MF的形成，并确定疾病病理的逆转是否与调节性巨噬细胞的诱导有关。我们将利用目标1中开发的“生物标记物”来确定R-MF在疾病解决过程中在组织中的持久性。我们将通过添加外源‘重新编程’信号(目标1)或通过促进ATP转化为腺苷(目标2)来产生R-MF。在这些研究中要检验的核心假设是，巨噬细胞的生理学可以被可靠地和可预测地操纵，并且R-MF可以被利用来改变免疫反应和影响疾病结果。通过诱导调节性巨噬细胞，我们可以预防或逆转自身免疫病理。通过删除调节性巨噬细胞，我们可以增强免疫力。

DESCRIPTION (provided by applicant): This application seeks to study a subpopulation of activated macrophages that we've identified with potent immunoregulatory activity. We will determine if we can exploit these regulatory macrophages (R-Mf) to develop a novel class of anti-inflammatory therapeutics. In Aim 1, we will characterize regulatory macrophages, and identify a panel of R-Mf-specific biomarkers to develop a "signature" for these cells. These biomarkers will be used to determine the various "reprogramming" signals that can give rise to regulatory macrophages and they will enable the identification of these cells in tissue during disease. We propose that the depletion or induction of R-Mf represent new approaches to treat diseases. In Aim 2, we will examine the conversion of classically activated macrophages (Ca- Mf) to regulatory macrophages. We propose that Ca-Mf can control their own activation state by secreting ATP and rapidly converting it to adenosine. Adenosine induces a regulatory macrophage phenotype. In the absence of this conversion, macrophage activation progresses uncontrolled, leading to inflammatory pathology. This represents a new paradigm in (controlling) macrophage activation. We will determine the role that macrophage ectoenzymes, CD39 and CD73, play in promoting the conversion of ATP to adenosine by engineering macrophages to overexpress or lack these ectoenzymes. The biomarkers developed in Aim 1 will help us to identify the induction of regulatory macrophages following their exposure to adenosine. In Aim 3, we will manipulate macrophages to improve human health. We will induce the formation of R-Mf and determine whether the reversal of disease pathology correlates with the induction of regulatory macrophages. We will utilize the "biomarkers" developed in Aim 1 to identify the persistence of R-Mf in tissue during the process of disease resolution. We will generate R-Mf by either adding exogenous 'reprogramming' signals (Aim 1) or by promoting the conversion of ATP to adenosine (Aim 2). The core hypothesis to be tested in these studies is that macrophage physiology can be reliably and predictably manipulated, and that R-Mf can be exploited to modify immune responses and affect disease outcomes. By inducing regulatory macrophages we can prevent or reverse autoimmune pathologies. By deleting regulatory macrophages we may enhance immunity.