Pommerolle Lenny, Beltramo Guillaume, Biziorek Leo, Truchi Marin, Dias Alexandre Magno Maneschy, Dondaine Lucile, Tanguy Julie, Pernet Nicolas, Goncalves Victor, Bouchard Alexanne, Monterrat Marie, Savary Grégoire, Pottier Nicolas, Ask Kjetil, Kolb Martin R J, Mari Bernard, Garrido Carmen, Collin Bertrand, Bonniaud Philippe, Burgy Olivier, Goirand Françoise, Bellaye Pierre-Simon
HSP-pathies Team, INSERM U1231 CTM Labex LIPSTIC and Label of Excellence from la Ligue National Contre le Cancer, Dijon, France.
Pneumology and Respiratory Intensive Care, CHU Dijon, Dijon, France.
Thorax. 2024 Nov 14;79(12):1124-1135. doi: 10.1136/thorax-2023-221168.
Interstitial lung diseases (ILDs) include a large number of diseases associated with progressive pulmonary fibrosis (PPF), including idiopathic pulmonary fibrosis (IPF). Despite the rarity of each of the fibrotic ILDs individually, they cumulatively affect a considerable number of patients. PPF is characterised by an excessive collagen deposition leading to functional decline.
Therapeutic options are limited to nintedanib and pirfenidone which are only able to reduce fibrosis progression. CD206-expressing M2 macrophages are involved in fibrosis progression, and whether they may be relevant therapeutic targets or biomarkers remains an open question.
In our study, CD206 lung macrophages were monitored in bleomycin-induced lung fibrosis in mice by combining flow cytometry, scRNAseq and in vivo molecular imaging using a single photon emission computed tomography (SPECT) radiopharmaceutical, Tc-tilmanocept. The antifibrotic effect of the inhibition of M2 macrophage polarisation with a JAK inhibitor, tofacitinib, was assessed in vivo. We demonstrate that CD206-targeted in vivo SPECT imaging with Tc-tilmanocept was able to accurately detect and quantify the increase in CD206 macrophages from early to advanced stages of experimental fibrosis and ex vivo in lung biopsies from patients with IPF. CD206-targeted imaging also specifically detected a decrease in CD206 lung macrophages on nintedanib and tofacitinib treatment. Importantly, early in vivo imaging of CD206 macrophages allowed the prediction of experimental lung fibrosis progression as well as nintedanib and tofacitinib efficacy.
These findings indicate that M2 macrophages may be relevant theranostic targets for personalised medicine for patients with PPF.
间质性肺疾病（ILDs）包括大量与进行性肺纤维化（PPF）相关的疾病，其中包括特发性肺纤维化（IPF）。尽管每种纤维化ILDs单独来看都很罕见，但它们累计影响了相当数量的患者。PPF的特征是胶原蛋白过度沉积导致功能下降。
治疗选择仅限于尼达尼布和吡非尼酮，它们只能减缓纤维化进展。表达CD206的M2巨噬细胞参与纤维化进展，它们是否可能是相关的治疗靶点或生物标志物仍是一个悬而未决的问题。
在我们的研究中，通过结合流式细胞术、单细胞RNA测序（scRNAseq）以及使用单光子发射计算机断层扫描（SPECT）放射性药物锝-替莫西肽进行体内分子成像，对博来霉素诱导的小鼠肺纤维化中的CD206肺巨噬细胞进行了监测。在体内评估了用JAK抑制剂托法替布抑制M2巨噬细胞极化的抗纤维化作用。我们证明，用锝-替莫西肽进行的靶向CD206的体内SPECT成像能够准确检测和量化实验性纤维化从早期到晚期阶段以及IPF患者肺活检组织离体时CD206巨噬细胞的增加。靶向CD206的成像还特异性地检测到尼达尼布和托法替布治疗后CD206肺巨噬细胞的减少。重要的是，对CD206巨噬细胞进行早期体内成像能够预测实验性肺纤维化的进展以及尼达尼布和托法替布的疗效。
这些发现表明，M2巨噬细胞可能是PPF患者个性化医疗的相关诊疗靶点。
