CD160+ intraepithelial lymphocytes and CCRL2+ macrophages drive differential repair in cardiac and liver injuries.

The regenerative capacities of organs in adult mammals vary significantly. Unlike the liver, which possesses remarkable regenerative potential, the repair of cardiac injuries has long posed a critical medical challenge. Recent studies have highlighted the pivotal role of the immune microenvironment in repairing damage in these tissues, but the key cell types and their mechanisms of action remain incompletely understood. In this study, we established a model of concurrent physical trauma to the hearts and livers of adult mice, revealing that these two injured tissues drive distinct immune microenvironments. The liver primarily accumulates lymphocytes, whereas the heart recruits macrophages and neutrophils. Notably, CD160+CD8+ intraepithelial lymphocytes in the liver were found to suppress fibrosis postliver injury and mitigate cardiac fibrosis when delivered via hydrogel patches. Conversely, in response to heart trauma, recruited inflammatory macrophages not only express proinflammatory cytokines but also coexpress CCRL2. While CCRL2 did not directly alter the intensity of the inflammatory response, it facilitated fibroblast proliferation and migration through its interaction with Na+/K+-ATPase on fibroblasts. These findings elucidated the contrasting immune microenvironments between the heart and liver following injury and provided novel insights and strategies for diagnosing and treating cardiac diseases.