Elastin receptor (S-gal) occupancy by elastin peptides modulates T-cell response during murine emphysema

Abstract

Chronic obstructive pulmonary disease and emphysema are associated with increased elastin peptides (EP) production because of excessive breakdown of lung connective tissue. We recently reported that exposure of mice to EP elicited hallmark features of emphysema. EP effects are largely mediated through a receptor complex that includes the elastin-binding protein spliced-galactosidase (S-gal). In previous studies, we established a correlation between cytokine production and S-gal protein expression in EP-treated immune cells. In this study, we investigated the S-gal-dependent EP effects on T-helper (Th) and T-cytotoxic (Tc) responses during murine EP-triggered pulmonary inflammation. C57BL/6J mice were endotracheally instilled with the valine-glycine-valine-alanine-proline-glycine (VGVAPG) elastin peptide, and, 21 days after treatment, local and systemic T-lymphocyte phenotypes were analyzed at cytokine and transcription factor expression levels by multicolor flow cytometry. Exposure of mice to the VGVAPG peptide resulted in a significant increase in the proportion of the CD4 and CD8 T cells expressing the cytokines IFN-γ or IL-17a and the transcription factors T-box expressed in T cells or retinoic acid-related orphan receptor-γt (RORγt) without effects on IL-4 and Gata-binding protein 3 to DNA sequence [A/T]GATA[A/G] expression. These effects were maximized when each T-cell subpopulation was challenged ex vivo with EP, and they were inhibited in vivo when an analogous peptide antagonizing the EP/S-gal interactions was instilled together with the VGVAPG peptide. This study demonstrates that, during murine emphysema, EP-S-gal interactions contribute to a Th-1 and Th-17 proinflammatory T-cell response combined with a Tc-1 response. Our study also highlights the S-gal receptor as a putative pharmacological target to modulate such an immune response.

Emphysema-associated Autoreactive Antibodies Exacerbate Post–Lung Transplant Ischemia–Reperfusion Injury

“…Although our data support a role for antibody-induced injury, we acknowledge that further studies are needed to see how preexisting ECM T-cell autoreactivity, as described in humans and mice (47,48), will impact post-transplant outcomes. Given the complex role of T cells in organ rejection, a role that is even further obscured in the context of lung transplantation as Kreisel and colleagues have demonstrated through a series of publications (49-51), we believed that the task of addressing the mechanisms by which CS alters T-cell subsets and effector/memory/regulatory functions was beyond the scope of our present study.…”

Riboflavin photo‐cross‐linking method for improving elastin stability and reducing calcification in bioprosthetic heart valves

“…Elastin provides the ability of BHVs to rapidly return to the resting positions during diastole. Elastin is mainly composed of amino acid including glycine, valine, alanine, and proline and scarce in reactive groups. The commercially available GLUT fixative has been known to be less effective in cross‐linking elastin due to the lack of reactive groups to the aldehyde group .…”

Lymphatic Pump Manipulation in Patients with Chronic Obstructive Pulmonary Disease

“…The speed of the lymphatic flow is approximately 125 mL/h in a person at rest but can increase by a factor of 10 during active movements [12][13]. Another passive mechanism that can manage lymphatic flow is oxygen pressure, particularly at low gradients (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40); if the oxygen pressure is higher, the lymphatic flow slows down. Temperature can also influence the speed of the lymphatic flow; the function of the lymphatic system is optimal at temperatures ranging between 32°C and 37°C, and probably acts via extracellular osmotic changes.…”

“…T lymphocytes stimulate the degradation of elastin, one of the most important causes of emphysema in patients with COPD. This form of degradation is stimulated in turn by the recruitment of IL-17 (synthesized by the indirect stimulation of lymphatic dendritic cells) and interferon-gamma (stimulated by type 1 innate lymphatic cells) [32][33]. Collectively, these events create a vicious circle.…”