CD44-deficiency attenuates the immunologic responses to LPS and delays the onset of endotoxic shock-induced renal inflammation and dysfunction.

Elena Rampanelli,Steven T Pals,Sandrine Florquin,Gwendoline J D Teske,Sander P J Joosten,Nike Claessen,Mark C Dessing,Jaklien C Leemans,Jian Fu

doi:10.1371/journal.pone.0084479

Elena Rampanelli, Steven T Pals + Show 7 more

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https://doi.org/10.1371/journal.pone.0084479

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Abstract

Acute kidney injury (AKI) is a common complication during systemic inflammatory response syndrome (SIRS), a potentially deadly clinical condition characterized by whole-body inflammatory state and organ dysfunction. CD44 is a ubiquitously expressed cell-surface transmembrane receptor with multiple functions in inflammatory processes, including sterile renal inflammation. The present study aimed to assess the role of CD44 in endotoxic shock-induced kidney inflammation and dysfunction by using CD44 KO and WT mice exposed intraperitoneally to LPS for 2, 4, and 24 hours . Upon LPS administration, CD44 expression in WT kidneys was augmented at all time-points. At 2 and 4 hours, CD44 KO animals showed a preserved renal function in comparison to WT mice. In absence of CD44, the pro-inflammatory cytokine levels in plasma and kidneys were lower, while renal expression of the anti-inflammatory cytokine IL-10 was higher. The cytokine levels were associated with decreased leukocyte influx and endothelial activation in CD44 KO kidneys. Furthermore, in vitro assays demonstrated a role of CD44 in enhancing macrophage cytokine responses to LPS and leukocyte migration. In conclusion, our study demonstrates that lack of CD44 impairs the early pro-inflammatory cytokine response to LPS, diminishes leukocyte migration/chemotaxis and endothelial activation, hence, delays endotoxic shock-induced AKI.

Highlights

Systemic inflammatory response syndrome (SIRS) is a potentially deadly clinical condition associated with systemic activation of multiple inflammatory pathways that often results in severe organ dysfunction and failure, including acute renal failure (ARF) [1,2]
Since sepsis is defined as a systemic inflammatory response syndrome, we evaluated the plasma pro-inflammatory cytokine levels, which are known to be upregulated in septic patients and correlate with mortality [2,35], and the cytokine expression in kidneys
Through extrarenal Toll-like receptor-4 (TLR-4), LPS causes an early rise in cytokines, which in turn activate a second level of inflammatory cascade including further cytokine production, nitric oxide (NO) synthesis, upregulation of cell adhesion molecules that results in inflammatory cells migration into tissues, endothelial injury and organ damage [2]

Summary

Introduction

Systemic inflammatory response syndrome (SIRS) is a potentially deadly clinical condition associated with systemic activation of multiple inflammatory pathways that often results in severe organ dysfunction and failure, including acute renal failure (ARF) [1,2]. LPS-induced TLR-4 activation promotes an early rise in pro-inflammatory cytokine production in many cell types, especially in mononuclear cells. The resulting cytokines such as tumor necrosis factor (TNF-α), interleukin (IL)-1 and IL-6, mediate renal injury directly or through the action of reactive oxygen/nitrogen species, caspases and nitric oxide (NO) [2,6] that causes renal vasoconstriction with sodium and water retention, which is the predominant pathogenic factor in early sepsis-related ARF [3]

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