Lung T Lymphocyte Trafficking and Activation during Ischemic Acute Kidney Injury

Abstract

Despite advances in renal replacement therapy, the mortality rate for acute kidney injury (AKI) remains unacceptably high, likely owing to extrarenal organ dysfunction. Kidney ischemia–reperfusion injury (IRI) activates cellular and soluble mediators that facilitate organ crosstalk and induce caspase-dependent lung apoptosis and injury through a TNFR1-dependent pathway. Given that T lymphocytes mediate local IRI in the kidney and are known to drive TNFR1-mediated apoptosis, we hypothesized that T lymphocytes activated during kidney IRI would traffic to the lung and mediate pulmonary apoptosis during AKI. In an established murine model of kidney IRI, we identified trafficking of CD3+ T lymphocytes to the lung during kidney IRI by flow cytometry and immunohistochemistry. T lymphocytes were primarily of the CD3+CD8+ phenotype; however, both CD3+CD4+ and CD3+CD8+ T lymphocytes expressed CD69 and CD25 activation markers during ischemic AKI. The activated lung T lymphocytes did not demonstrate an increased expression of intracellular TNF-α or surface TNFR1. Kidney IRI induced pulmonary apoptosis measured by caspase-3 activation in wild-type controls, but not in T cell-deficient (Tnu/nu) mice. Adoptive transfer of murine wild-type T lymphocytes into Tnu/nu mice restored the injury phenotype with increased cellular apoptosis and lung microvascular barrier dysfunction, suggesting that ischemic AKI-induced pulmonary apoptosis is T cell dependent. Kidney–lung crosstalk during AKI represents a complex biological process, and although T lymphocytes appear to serve a prominent role in the interorgan effects of AKI, further experiments are necessary to elucidate the specific role of activated T cells in modulating pulmonary apoptosis.

Transcriptional regulation of CD4 gene expression in porcine kidney epithelial cells by virus-like double-stranded RNA and DNA methyltransferase inhibitor

“…T lymphocytes that express the CD4 marker, primarily of the CD3 + T lymphocyte phenotype, have been shown to be activated during acute kidney injury (Lie et al, 2012). Recruitment and activation of CD4 + T lymphocytes after kidney injury could be the very important early event that mediates the onset of renal fibrogenesis (Liu et al, 2012).…”

Mechanisms and mediators of lung injury after acute kidney injury

“…Specifically, T-cell recruitment to the lung increases by 24 h after AKI, T-cell deficient mice exhibit reduced caspase-3 activation and less pulmonary oedema compared to control mice, and reconstitution of T cells can elicit lung injury in T-cell-deficient mice, as judged by increased caspase-3 activation and increased pulmonary oedema. 122 T cells seem to facilitate lung endothelial apoptosis via caspase-3, leading to lung endothelial cell death and non-cardiogenic pulmonary oedema. 122 The role of other leucocytes, such as neutrophils and macrophages, in AKI-mediated lung injury is less clear.…”

“…122 T cells seem to facilitate lung endothelial apoptosis via caspase-3, leading to lung endothelial cell death and non-cardiogenic pulmonary oedema. 122 The role of other leucocytes, such as neutrophils and macrophages, in AKI-mediated lung injury is less clear. To date, no studies have examined the effects of neutrophil depletion on lung injury after AKI, and studies have only assessed neutrophil infiltration as a marker of lung injury after AKI.…”

“…Circulating HMGB1 mediates lung inflammation, in part via TLR4 activation, leading to neutrophil accumulation and non-cardiogenic pulmonary oedema T cells T-cell recruitment to the lung is increased within 24 h after AKI 122 T-cell deficient mice had less caspase-3 activation and less pulmonary oedema 122 Reconstitution of T cells to T-cell deficient mice restored lung injury as judged by increased caspase-3 activation and increased pulmonary oedema 122 T cells are recruited to the lung within 24 h of AKI onset and mediate lung endothelial apoptosis via caspase-3, leading to lung endothelial cell death and non-cardiogenic pulmonary oedema Abbreviation: AKI, acute kidney injury.…”

“…The most well studied mediators of lung injury after AKI, namely IL-6, TNFR1 and caspase-3 mediated apoptosis, and T cells 122,123 are discussed in detail below.…”