Untangling Local Pro-Inflammatory, Reparative, and Regulatory Damage-Associated Molecular-Patterns (DAMPs) Pathways to Improve Transplant Outcomes

Abstract

Detrimental inflammatory responses after solid organ transplantation are initiated when immune cells sense pathogen-associated molecular patterns (PAMPs) and certain damage-associated molecular patterns (DAMPs) released or exposed during transplant-associated processes, such as ischemia/reperfusion injury (IRI), surgical trauma, and recipient conditioning. These inflammatory responses initiate and propagate anti-alloantigen (AlloAg) responses and targeting DAMPs and PAMPs, or the signaling cascades they activate, reduce alloimmunity, and contribute to improved outcomes after allogeneic solid organ transplantation in experimental studies. However, DAMPs have also been implicated in initiating essential anti-inflammatory and reparative functions of specific immune cells, particularly Treg and macrophages. Interestingly, DAMP signaling is also involved in local and systemic homeostasis. Herein, we describe the emerging literature defining how poor outcomes after transplantation may result, not from just an over-abundance of DAMP-driven inflammation, but instead an inadequate presence of a subset of DAMPs or related molecules needed to repair tissue successfully or re-establish tissue homeostasis. Adverse outcomes may also arise when these homeostatic or reparative signals become dysregulated or hijacked by alloreactive immune cells in transplant niches. A complete understanding of the critical pathways controlling tissue repair and homeostasis, and how alloimmune responses or transplant-related processes disrupt these will lead to new immunotherapeutics that can prevent or reverse the tissue pathology leading to lost grafts due to chronic rejection.

Keywords: alarmins; damage-associated molecular patterns; immunometabolism; ischemia–reperfusion injury; macrophage; regulatory T cell; tissue repair and fibrosis; transplantation.

Figure 1

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.

Figure 2

DAMP may contribute to CR after Tx in several scenarios. (A) The alloreactive response of innate and adaptive cells may sustain the pro-inflammatory phase and lead to a failure to fully transition through the resolution phase and complete the repair phase. In this scenario, CR represents a failure to resolve and repair, leading to residual graft damage and failure to restore tissue homeostasis. Alternatively, these changes may cause an overzealous counter-responses initiated by reparative Treg and reparative macrophages in responses to regulatory and reparative DAMPs released by an unresolved allogeneic wound. (B) Alternatively, lost or depleted reparative and regulatory cells due to ischemia or alloimmune responses may lead to a failed resolution phase leading to residual graft damage. This scenario may also arise from a depletion of local reparative and regulatory DAMPs over time. In this case, CR would represent a failure to restore tissue homeostasis due to persisting graft damage.