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. 2021 Feb 23;12:611910. doi: 10.3389/fimmu.2021.611910

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Copyright © 2021 Dwyer and Turnquist

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Impact of pro-inflammatory versus reparative and regulatory DAMPs on immune cells during inflammation, resolution, and repair phases after tissue injury. (A) Recruited CCR2⁺ monocytes and the macrophages derived from them participate in a highly regulated, immune-mediated tissue repair process shaped by 1. Pro-inflammatory and 2. Reparative and Regulatory DAMPs. These also act on Treg and potentially resident macrophages to support the survival and function of these immune cells. (B) This process can be divided into three overlapping phases, including a: 1. pro-inflammatory phase (red), 2. resolution phase (blue), and 3. repair phase (green). In the first phase, pro-inflammatory DAMPs act on monocytes and macrophages to generate or support the function of highly phagocytic, inflammatory macrophages that use robust production of NO and pro-inflammatory cytokines to mediate the removal of any pathogens and damaged necrotic tissue. The transition to the resolution phase involves efferocytosis, or the phagocytosis of apoptotic cells, by macrophages receiving input from reparative and regulatory DAMPs and type 2 cytokines. These can both block the impact of pro-inflammatory stimuli on macrophages and contribute to the generation of Treg that support local immune suppression. The final phase involves little pro-inflammatory DAMP activity. It is dominated by reparative and regulatory DAMPs macrophage metabolism enabling the function of reparative and regulatory macrophages, such as secretion of cytokines, effector molecules, and growth factors that mediate responses in stromal, parenchymal cells, and stem cells to facilitate tissue repair. Regulatory and reparative DAMPs also act on Treg, which support the generation of reparative and regulatory macrophages and contribute growth factors to the repair environment. Reparative and Regulatory DAMP most likely also act on resident macrophages that are important for injury resolution and re-establishment and maintenance of tissue homeostasis. Abbreviations used: Areg, Amphiregulin; ATP, Adenosine Triphosphate; CCR2, CC Motif Receptor 2; DAMP, damage-associated molecular pattern; gDNA, Genomic DNA; HSP, Heat Shock Protein; HMGB1, High-mobility group box 1; IL, Interleukin; Ly6C, Lymphocyte antigen 6 complex, locus C1; mDNA, Mitochondrial DNA; NO, Nitric Oxide; SPM, Specialized pro-resolving mediators;TGF, Transforming growth factor; Treg, Regulatory T cell.