Alarmins and Their Receptors as Modulators and Indicators of Alloimmune Responses

Abstract

Cell damage and death releases alarmins, self-derived immunomodulatory molecules that recruit and activate the immune system. Unfortunately, numerous processes critical to the transplantation of allogeneic materials result in the destruction of donor and recipient cells and may trigger alarmin release. Alarmins, often described as damage-associated molecular patterns, together with exogenous pathogen-associated molecular patterns, are potent orchestrators of immune responses; however, the precise role that alarmins play in alloimmune responses remains relatively undefined. We examined evolving concepts regarding how alarmins affect solid organ and allogeneic hematopoietic cell transplantation outcomes and the mechanisms by which self molecules are released. We describe how, once released, alarmins may act alone or in conjunction with nonself materials to contribute to cytokine networks controlling alloimmune responses and their intensity. It is becoming recognized that this class of molecules has pleotropic functions, and certain alarmins can promote both inflammatory and regulatory responses in transplant models. Emerging evidence indicates that alarmins and their receptors may be promising transplantation biomarkers. Developing the therapeutic ability to support alarmin regulatory mechanisms and the predictive value of alarmin pathway biomarkers for early intervention may provide opportunities to benefit graft recipients.

Keywords: basic (laboratory) research/science; biomarker; bone marrow/hematopoietic stem cell transplantation; cytokines/cytokine receptors; graft-versus-host disease (GVHD); heart transplantation/cardiology; immunobiology; innate immunity; translational research/science.

Figure 1. Cytokine Networks Shaping Alarmin Functions in Allotransplantation

Tissue damage and cell death, particularly of the barrier tissues, results in the release of alarmins, including HMGB1, IL-1α, IL-33, and free heme. In the presence of PAMPs arising from infiltrating pathogens or commensal microbes, alarmins augment IL-12p70, IL-1β, IL-6, IL-18, and IL-23 production by TLR/IL-1R stimulated antigen-presenting cells (APC), including dendritic cells (DC). IL12p70 stimulates Th1 polarization and immune cell IFNγ production. In addition, IL-12p70 induces ST2 on NK and CD8⁺ T-cells, thus enabling them to respond to IL-33 with augmented IFNγ. IL-33 signaling may also facilitate CD8⁺ T-cells IFNγ secretion by supporting their responses to IL-18 by upregulating the IL-18 receptor. In addition to stabilizing the Th17 polarization of CD4⁺ T-cells, IL-23 also renders ST2⁺ Treg less responsive to IL-33. IL-12p70-stimulated T cells are resistant to regulation. However, in the absence of PAMPs, IL-33 does not cause DC pro-inflammatory cytokine production, but instead stimulates them to secrete IL-2 which works with IL-33 to expand Treg populations, particularly the subset expressing ST2, which is both suppressive and implicated in tissue repair.