T cells modulate neutrophil-dependent acute renal failure during endotoxemia: Critical role for CD28

Kai Singbartl, Susanne Große Bockhorn, Alexander Zarbock, Mirco Schmolke, Hugo Van Aken

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Sepsis still represents a leading cause of acute renal failure (ARF). Both lymphocytes and neutrophils (PMN) have been proposed as crucial mediators during sepsis. For further elucidation of the mechanisms of interactions between them, a murine model of LPS-induced ARF was used. In wild-type mice (WT), LPS administration led to a strong influx of PMN into the kidney (2.8-fold greater renal myeloperoxidase activity after 24 h) and to severe ARF (3.3-fold higher plasma creatinine concentrations after 24 h). By contrast, mice that were gene deficient for CD28 (CD28-/-), a co-stimulatory molecule for T cell activation, exhibited only minor renal dysfunction (50% protection compared with WT) and almost no PMN recruitment. When PMN- depleted, both WT and CD28-/- developed only mild ARF, similar to untreated CD28 -/-. Flow cytometry demonstrated that CD28 was vastly expressed on CD3+ cells but not on PMN. Injecting wild-type CD3+ cells into CD28-/- before LPS injection abolished the protection seen before. At baseline, both WT and CD28-/- displayed similar plasma concentrations of keratinocyte-derived chemokine (KC), a growth-related oncogene 1 gene product and PMN-specific chemokine. As opposed to WT, CD28-/- showed a greatly attenuated increase in plasma KC 4 h after LPS (2.5- versus 138.5-fold over controls, respectively). Moreover, CD28-/- showed less intense upregulation of renal growth-related oncogene 1 mRNA expression. Immunohistochemistry revealed considerable PMN but no T cell infiltrates in the kidney after LPS injection. In a PMN-dependent model of endotoxemic ARF, T cells, via the CD28 pathway, modulate kidney function and renal PMN recruitment. The effect on PMN is a remote one and presumably due to altered expression of PMN-specific chemokines.

Original languageEnglish (US)
Pages (from-to)720-728
Number of pages9
JournalJournal of the American Society of Nephrology
Volume16
Issue number3
DOIs
StatePublished - 2005

All Science Journal Classification (ASJC) codes

  • Nephrology

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