Macrophages, not neutrophils, infiltrate skeletal muscle in mice deficient in P/E selectins after mechanical reloading

Abstract

Our objective was to test the hypothesis that endothelial selectins, P and E selectins, are necessary for leukocyte migration after muscle injury from unloading/reloading. Mice hindlimbs were suspended for 10 days followed by reloading periods of 6 or 24 h after which the soleus muscle was dissected. Light microscopic observations showed that macrophages, but not neutrophils, were able to invade soleus muscles in mice deficient in P/E selectins (P/E-/-) during reloading periods. The recruitment efficiency of neutrophils after 6 and 24 h of reloading was minimal in P/E-/- mice relative to unloaded animals. The recruitment of macrophages in the soleus muscle was preserved in P/E-/- mice. The concentration of macrophages increased by 8.1-fold compared with unloaded muscles in double-mutant mice after 24 h of reloading. The accumulation of macrophages in reloaded muscles did not lead to fiber necrosis. Together, these findings indicate that macrophages can invade skeletal muscle through cellular mechanisms that do not involve P/E selectins during skeletal muscle reloading.

Multi-cell Agent-based Simulation of the Microvasculature to Study the Dynamics of Circulating Inflammatory Cell Trafficking

“…The data indicated a prominent role for ICAM-1 and VCAM-1 in monocyte rolling and adhesion, and a less important role for the selectins in these processes. These results are consistent with independent experimental studies performed in the corresponding set of knockout mice, 26,42 suggesting that our simulation is capable of independently predicting key events during monocyte trafficking.…”

“…The maintained extravasation levels are a non-intuitive result, which is consistent with the literature that indicates a decreased dependence of monocytes on selectin-mediated rolling for firm adhesion. 26,42 A critical next step is to match these in silico predictions with in vivo experimentation on selectin . L-, E-and P-selectins, and PSGL-1 knockouts showed no significant differences from the control group.…”

“…For example, neutrophils will fail to progress through the adhesion cascade in the absence of selectins, whereas monocytes have been shown to be less dependent on selectinmediated rolling and are able to transmigrate through integrin activation alone. 26,42 Traditionally however, it is believed that selectin-mediated rolling allows an inflammatory cell to 'survey' the endothelium for activating stimuli, which ultimately leads to integrin activation once a theoretical 'threshold activation level' is reached. 60 Thus, it is a unique pairing of molecular functionality that controls leukocyte adhesion: the selectins mediate the tethering and rolling of leukocytes, and the integrins utilize selectin-mediated rolling for more efficient activation and firm adhesion.…”

“…This is in agreement with in vivo experiments that indicate monocytes possess a decreased dependence on selectinmediated rolling compared to neutrophils. 26 Simulated knockouts of individual integrins predicted varying degrees of dependence of firm adhesion on them, while knocking out both VCAM-1 and ICAM-1 resulted in no firm adhesion.…”

Genomic organization, promoter activity, and expression of the human choline transporter-like protein 1

“…Importantly, skeletal muscle has a remarkable capacity for regeneration largely depending on the number of available satellite cells and their proliferative capacity (34). Injured or diseased muscle also demonstrates increased macrophage cell accumulation; the extent of macrophage accumulation correlates with both the clearance of protein after injury and efficiency of regeneration (13). The increased CTL1 protein in multiple human myopathies (Fig.…”