老化, 癌症, 和發炎

《Ageing Res Rev》（2017年7月）評論文章：老化與癌症：巨噬細胞和中性粒細胞的角色 作者：Connie Jackaman、Federica Tomay、Lelinh Duong、Norbaini Bintu Abdol Razak、Fiona J Pixley、Pat Metharom、Delia J Nelson 摘要 免疫功能受損已與老年人健康狀況下降和癌症發病率增加有關。然而，免疫系統與年齡相關的變化尚不完全清楚。中性粒細胞和巨噬細胞是第一道防禦線，但它們的吞噬病原體的能力在老化過程中減弱。細胞毒性T淋巴細胞在消除腫瘤中起著關鍵作用，但T細胞功能在老化過程中也受到損害。巨噬細胞可以調節T細胞反應，並可能取決於巨噬細胞在微環境信號下所採取的功能表型。這可以從促發炎、抗腫瘤的M1型巨噬細胞到抗發炎、促腫瘤的M2型巨噬細胞。健康老年人的脂肪組織和肝組織中的巨噬細胞表現出更多促發炎的M1表型，而免疫抑制的M2型巨噬細胞在老年淋巴組織、肺部和肌肉中增加。這些M2樣巨噬細胞對刺激的反應發生變化。最近的研究表明，中性粒細胞也調節T細胞功能，並且像巨噬細胞一樣，中性粒細胞的功能也會隨著年齡變化而調節。年齡修飾的組織特異性巨噬細胞和中性粒細胞可能導致與失調的巨噬細胞介導的免疫抑制相關的慢性低度發炎，這些因素共同導致多種病理狀態的發展，包括癌症。本文討論了在健康老化和癌症中巨噬細胞和中性粒細胞生物學的最新進展。

關鍵詞：老化；癌症；巨噬細胞；中性粒細胞；腫瘤微環境。

Aging and cancer: The role of macrophages and neutrophils

Aging and immunosenescence

The global population is aging, leading to increased life expectancy. However, aging is associated with deteriorating health and an increased risk of cancer, placing enormous pressure on health infrastructures. Furthermore, aging is associated with declining immune function. This process, known as immunosenescence (Pawelec and Solana, 1997) is accompained by the onset of a state of low-grade chronic inflammation termed ‘inflammaging’ (Franceschi et al., 2000) characterised by increased levels


《Macrophages in immunoregulation and therapeutics》（Signal Transduct Target Ther，2023年）評論文章： 作者：Shanze Chen、Abdullah F U H Saeed、Quan Liu、Qiong Jiang、Haizhao Xu、Gary Guishan Xiao、Lang Rao、Yanhong Duo 摘要 巨噬細胞存在於各種組織、多個體腔和黏膜表面周圍，是先天免疫系統對抗多種病原體和癌症的重要組成部分。巨噬細胞具有二元的M1/M2巨噬細胞極化狀態，在多種免疫任務中通過內在信號級聯起著核心作用，因此必須得到精確調節。關於巨噬細胞信號和免疫調節的許多關鍵問題仍待揭示。此外，隨著對腫瘤相關巨噬細胞生物學的深入理解，它們在臨床上的重要性越來越被廣泛認識。此外，它們是腫瘤微環境的一部分，參與調節包括血管生成、細胞外基質轉化、癌細胞增殖、轉移、免疫抑制以及對化療和檢查點阻斷免疫療法的抗藥性等多種過程。在這篇文章中，我們討論了巨噬細胞極化和信號傳遞中的免疫調節、機械應力和調節、代謝信號通路、線粒體和轉錄、表觀遺傳調節。此外，我們廣泛探討了巨噬細胞在細胞外陷阱中的作用以及自噬和衰老在調節巨噬細胞功能方面的重要作用。此外，我們討論了巨噬細胞介導的免疫調節在自身免疫疾病和腫瘤發生中的最新進展。最後，我們討論了以巨噬細胞為靶向的治療，以描繪在健康和疾病中治療策略的前景性目標。 © 2023. 作者（們）。 

Below, we summarize some of the most critical factors which are relevant to macrophage polarization, including STAT family, NF-κB, Krüppel-like factors, IFN regulatory factors, peroxisome PPAR, HIF.18 

The induction of repolarization of macrophages is a proven and effective method.370,371 TAMs polarized in the M1 state are linked to anticancer responses, while TAMs polarized in the M2 state are related to protumor activities. IFN, CD40 agonists, PI3Kγ/mTOR/DICER inhibitors, agonists of TLR4/7/8/9, methionine sulfoximine, HDAC inhibitors, and antibodies against macrophage receptors with collagenous structures are some of the stimuli that might cause M1 polarization. In contrast, substances that hinder M2 polarization, such as CSF1R inhibitors, corosolic acid, omeprazole, Gpr132 inhibitors, MEK/STAT3 inhibitors, fast-mimicking diets, and antibodies against IL-4, IL-4Rα, and IL-13, are also able to diminish the amount of tumor burden.372 

In addition to other functions of macrophages, aging is a multifaceted strategy that fundamentally impacts all organs. Deteriorated cellular repair roots augmented injury at genomic and proteomic stages upon aging. Tissue macrophages are central inflammatory cytokine fabricators, additional stimulators, and regulators of aging inflammation. Repair damage may contribute to systemic changes in metabolism and the production of pro-inflammatory cytokines, resulting in lower-grade inflammation or ‘inflammation’.352 Comprehending the interaction between macrophage and immune regulation approaches and tumorigenesis is central to gaining precise functions. It is also evident that the numerous immune signaling mechanisms are robustly intertwined, and feedback loops play a role in intensifying or inhibiting immune responses. 

Review 

Trends Immunol




. 2019 Feb;40(2):113-127. doi: 10.1016/j.it.2018.12.007. Epub 2019 Jan 6.

Metabolic Alterations in Aging Macrophages: Ingredients for Inflammaging?

Adriaan A van Beek 1, Jan Van den Bossche 2, Pier G Mastroberardino 3, Menno P J de Winther 4, Pieter J M Leenen 5

Affiliations expand

Abstract

Aging is a complex process with an impact on essentially all organs. Declined cellular repair causes increased damage at genomic and proteomic levels upon aging. This can lead to systemic changes in metabolism and pro-inflammatory cytokine production, resulting in low-grade inflammation, or 'inflammaging'. Tissue macrophages, gatekeepers of parenchymal homeostasis and integrity, are prime inflammatory cytokine producers, as well as initiators and regulators of inflammation. In this opinion piece, we summarize intrinsic alterations in macrophage phenotype and function with age. We propose that alternatively activated macrophages (M2-like), which are yet pro-inflammatory, can accumulate in tissues and promote inflammaging. Age-related increases in endoplasmic reticulum stress and mitochondrial dysfunction might be cell-intrinsic forces driving this unusual phenotype.

Keywords: aging; cell metabolism; epigenetics; inflammation; macrophages.