T cells modulate neutrophil-dependent acute renal failure during endotoxemia: critical role for CD28.
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.
Singbartl
Kai
K
Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Universitätsklinikum Münster, Albert Schweitzer Strasse 33, 48129 Münster, Germany. singbartl@uni-muenster.de
Bockhorn
Susanne Grosse
SG
Zarbock
Alexander
A
Schmolke
Mirco
M
Van Aken
Hugo
H
D058186:Acute Kidney Injury / Q000276:immunology* / Q000473:pathology; D019264:Adoptive Transfer; D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D018925:Chemokines / Q000235:genetics; D019446:Endotoxemia / Q000276:immunology* / Q000473:pathology; D015870:Gene Expression / Q000276:immunology; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D018106:CD28 Antigens; D018925:Chemokines; D008070:Lipopolysaccharides