Tissue injury or inflammation releases damage-associated molecular patterns (DAMPs) and alarmins that are recognized by tissue-resident macrophages via pattern recognition receptors (PRRs), leading to recruitment of circulating monocytes through the CCL2/CCR2 chemokine axis. Recruited Ly6C^hi (mouse) or CD14^hi (human) monocytes differentiate into monocyte-derived macrophages that polarize toward M1 or M2 states in response to local cues, including CD4⁺ Th cell cytokines, such as Th1-derived IFN-γ or Th2-derived IL-4 and IL-13. Under profibrotic conditions, Th17-derived interleukin-17A (IL-17A), granulocyte–macrophage colony-stimulating factor (GM-CSF), and megakaryocyte/platelet-derived CXC chemokine ligand 4 (CXCL4), together with transforming growth factor-β (TGF-β), drive differentiation of monocytes/macrophages into secreted phosphoprotein–positive (SPP1⁺) macrophages. These profibrotic SPP1⁺ macrophages, along with platelets, secrete mediators such as SPP1, connective tissue growth factor (CTGF), PDGF, and TGF-β, which activate fibroblasts and perivascular stromal cells, including glioma-associated oncogene homolog 1–positive (Gli1⁺) pericytes, leptin receptor–positive (LepR⁺) pericytes, PDGF receptor-β–positive (PDGFRβ⁺) progenitors, and hepatic stellate cells, depending on the tissue context. These cells differentiate into ECM-producing myofibroblasts that drive fibrotic remodeling. In addition, monocyte-derived fibrocytes also contribute to ECM deposition through IL-4–, IL-13–, and TGF-β–dependent signaling pathways.