Absence of CCR2 Promotes Proliferation of Alveolar Macrophages That Control Lung Inflammation in Acute Respiratory Distress Syndrome in Mice

Abstract

Acute respiratory distress syndrome (ARDS) consists of uncontrolled inflammation that causes hypoxemia and reduced lung compliance. Since it is a complex process, not all details have been elucidated yet. In a well-controlled experimental murine model of lipopolysaccharide (LPS)-induced ARDS, the activity and viability of macrophages and neutrophils dictate the beginning and end phases of lung inflammation. C-C chemokine receptor type 2 (CCR2) is a critical chemokine receptor that mediates monocyte/macrophage activation and recruitment to the tissues. Here, we used CCR2-deficient mice to explore mechanisms that control lung inflammation in LPS-induced ARDS. CCR2−/− mice presented higher total numbers of pulmonary leukocytes at the peak of inflammation as compared to CCR2+/+ mice, mainly by enhanced influx of neutrophils, whereas we observed two to six-fold lower monocyte or interstitial macrophage numbers in the CCR2−/−. Nevertheless, the time needed to control the inflammation was comparable between CCR2+/+ and CCR2−/−. Interestingly, CCR2−/− mice presented higher numbers and increased proliferative rates of alveolar macrophages from day 3, with a more pronounced M2 profile, associated with transforming growth factor (TGF)-β and C-C chemokine ligand (CCL)22 production, decreased inducible nitric oxide synthase (Nos2), interleukin (IL)-1β and IL-12b mRNA expression and increased mannose receptor type 1 (Mrc1) mRNA and CD206 protein expression. Depletion of alveolar macrophages significantly delayed recovery from the inflammatory insult. Thus, our work shows that the lower number of infiltrating monocytes in CCR2−/− is partially compensated by increased proliferation of resident alveolar macrophages during the inflammation control of experimental ARDS.

Targeting transitioning lung monocytes/macrophages as treatment strategies in lung disease related to environmental exposures

“…In endotoxin exposure models of lung injury, several studies have also demonstrated that there is a decrease in the endotoxininduced recruitment of peripheral blood monocytes, exudative macrophages, F4/80 + lung cells, lung neutrophils, and lung cell in ltrates in CCR2 KO mice as well as mice depleted of systemic monocytes by clodronate liposomes (25,(50)(51)(52)(53)(54). Our studies con rm the reduction in in ltrating monocytes/macrophages with both the CCR2 KO and the administration clodronate liposomes, but also simultaneously highlight striking differences in these modeling approaches to reduce pro brotic and in ammatory responses following LPS exposure.…”

“…CC motif chemokine receptor 2 (CCR2) is a critical facilitator of monocyte recruitment and activation via interaction with its high-a nity ligand CCL2 (23,24). CCR2 + monocytes play a critical role in the onset of in ammation and, upon reaching the in amed tissue, differentiate into phenotypically and functionally distinct macrophages, capable of modulating in ammatory responses (25).…”