Molecular imaging of chemokine-like receptor 1 (CMKLR1) in experimental acute lung injury

Abstract

The lack of techniques for noninvasive imaging of inflammation has challenged precision medicine management of acute respiratory distress syndrome (ARDS). Here, we determined the potential of positron emission tomography (PET) of chemokine-like receptor-1 (CMKLR1) to monitor lung inflammation in a murine model of lipopolysaccharide-induced injury. Lung uptake of a CMKLR1-targeting radiotracer, [ 64 Cu]NODAGA-CG34, was significantly increased in lipopolysaccharide-induced injury, correlated with the expression of multiple inflammatory markers, and reduced by dexamethasone treatment. Monocyte-derived macrophages, followed by interstitial macrophages and monocytes were the major CMKLR1-expressing leukocytes contributing to the increased tracer uptake throughout the first week of lipopolysaccharide-induced injury. The clinical relevance of CMKLR1 as a biomarker of lung inflammation in ARDS was confirmed using single-nuclei RNA-sequencing datasets which showed significant increases in CMKLR1 expression among transcriptionally distinct subsets of lung monocytes and macrophages in COVID-19 patients vs. controls. CMKLR1-targeted PET is a promising strategy to monitor the dynamics of lung inflammation and response to anti-inflammatory treatment in ARDS.

Preclinical Study in Mouse Thymus and Thymocytes: Effects of Treatment with a Combination of Sodium Dichloroacetate and Sodium Valproate on Infectious Inflammation Pathways

“…The significance of Cmklr1 (chemokine-like receptor-1) is not fully understood [ 127 , 128 ]. Cmklr1 deficiency reduces leukocyte recruitment to inflammation-damaged lungs [ 127 ].…”

“…On the other hand, activation of Cmklr1 in a murine model of virus-induced pneumonia improved viral clearance and antiviral antibody production, reduced the expression of pro-inflammatory mediators, reduced complications, and improved mouse survival [ 129 , 130 ]. While clinical data are still lacking, preclinical data suggest that Cmklr1 may be a lung inflammation biomarker in pneumonia patients [ 128 ]. The enzyme NOS2 (nitric oxide synthase 2) and reactive oxygen species (ROS) are players in inflammatory and immune responses.…”

Effects of Combined Treatment with Sodium Dichloroacetate and Sodium Valproate on the Genes in Inflammation- and Immune-Related Pathways in T Lymphocytes from Patients with SARS-CoV-2 Infection with Pneumonia: Sex-Related Differences

“…The clinical relevance of CMKLR1 as a marker of lung inflammation in ARDS was confirmed using RNA sequencing data, which showed that CMKLR1 expression is significantly increased in lung monocytes and macrophages in COVID-19 patients. CMKLR1-targeted PET is essential for monitoring the dynamics of lung inflammation and response to anti-inflammatory therapy [ 125 ]. The pro-inflammatory chemokine receptors CCR1, CCR2, CXCR3, and CX3CR1 mediate the immune response in the lung and are present in myeloid cells, T cells, and NK cells [ 126 ].…”

2-deoxy-2-[18F]fluoro-D-glucose Positron Emission Tomography to Monitor Lung Inflammation and Therapeutic Response to Dexamethasone in a Murine Model of Acute Lung Injury

“…For instance, the PET tracer [ 64 Cu]DOTA-ECL1i is reported to target CCR2-expressing monocytes [ 60 , 61 ], which have been demonstrated to be relevant in pulmonary inflammation and noninvasively monitors response to immunotherapies. Additionally, we have recently reported that [ 64 Cu]NODAGA-CG34, a PET tracer that selectively binds to chemokine-like receptor-1 (CMKLR1), detects the accumulation of monocyte-derived macrophages in the lungs of mice with ALI [ 62 ]. Other emerging molecular imaging targets include, α 4 β 1 integrin [ 63 ], leukocyte receptor CD11b [ 64 ], folate receptor-β [ 65 ], and translocator protein receptor [ 66 ], which have been successfully used for noninvasive detection of lung inflammation in ALI.…”