Hyaluronan Contributes to Bronchiolitis Obliterans Syndrome and Stimulates Lung Allograft Rejection through Activation of Innate Immunity

Abstract

Rationale: Although innate immunity is increasingly recognized to contribute to lung allograft rejection, the significance of endogenous innate ligands, such as hyaluronan (HA) fragments, in clinical or experimental lung transplantation is uncertain.Objectives: To determine if HA is associated with clinical bronchiolitis obliterans syndrome (BOS) in lung transplant recipients, and evaluate the effect of low-or high-molecular-weight HA on experimental lung allograft rejection, including dependence on innate signaling pathways or effector cells.Methods: HA concentrations were measured in bronchoalveolar lavage and plasma samples from lung recipients with or without established BOS. BOS and normal lung tissues were assessed for HA localization and expression of HA synthases. Murine orthotopic lung recipients with established tolerance were treated with low-or highmolecular-weight HA under varied experimental conditions, including Toll-like receptor (TLR) 2/4 and myeloid differentiation protein 88 deficiency and neutrophil depletion.Measurements and Main Results: HA localized within areas of intraluminal small airways fibrosis in BOS lung tissue. Moreover, transcripts for HA synthase enzymes were significantly elevated in BOS versus normal lung tissues and both lavage fluid and plasma HA concentrations were increased in recipients with BOS. Treatment with low-molecular-weight HA abrogated tolerance in murine orthotopic lung recipients in a TLR2/4-and myeloid differentiation protein 88-dependent fashion and drove expansion of alloantigen-specific T lymphocytes. Additionally, TLRdependent signals stimulated neutrophilia that promoted rejection. In contrast, high-molecular-weight HA attenuated basal allograft inflammation.Conclusions: These data suggest that accumulation of HA could contribute to BOS by directly activating innate immune signaling pathways that promote allograft rejection and neutrophilia.

Report of the ISHLT Working Group on Primary Lung Graft Dysfunction Part III: Mechanisms: A 2016 Consensus Group Statement of the International Society for Heart and Lung Transplantation

“…64,65 That function has been ascribed to inhibiting antigen-dependent responses, including experimental studies of immunosuppression-mediated lung transplant tolerance. 66–68 However, Tregs also have been reported to resolve experimental acute lung injury by inhibiting macrophage pro-inflammatory responses through augmenting neutrophil efferocytosis. 69 Moreover, they have been shown to limit fibroproliferation and augment alveolar epithelial repair.…”

Bioactive extracellular matrix fragments in lung health and disease

“…Among HA's effects, the induction of proteases or other matrix lytic enzymes is particularly relevant to its pathologic role. Low-molecular weight HA induces transcriptional upregulation and release of active forms of MMP12 (which cleaves elastin) and MMP9 (which cleaves collagen), each of which can facilitate further matrikine generation (78)(79)(80). HA activity impacts multiple aspects of cell migration, invasion, angiogenesis, and cellular differentiation; these activities of HA in lung physiology involve ligation of specific cellular receptors (76,81,82).…”

Organ-specific differences in achieving tolerance

“…Clinically, respiratory infections predispose lung grafts to immune-mediated failure (67) and infection with Pseudomonas aeruginosa results in neutrophilic graft infiltration that breaks established costimulation blockade-mediated lung allograft acceptance in mice (68). Low molecular weight hyaluronan, a damage-associated molecular pattern that is associated with chronic lung rejection in humans, breaks costimulation blockade-mediated acceptance of mouse pulmonary allografts (69). This abrogation of acceptance is dependent on neutrophilic graft infiltration and signaling via TLR2/TLR4 as well as MyD88 in the recipients.…”