Chemokine Regulation of Neutrophil Function in Surgical Inflammation

Abstract

Background: Morbidity and even mortality correlate closely with major injury that causes a systemic inflammatory response. Cytokines and bioactive molecules present at the inflammatory site induce this response and regulate neutrophil proinflammatory responses. The CXC chemokines, important for neutrophil recruitment and activation, include interleukin 8 (IL-8), granulocyte chemotactic protein 2 (GCP-2), and epithelial cell-derived neutrophil attractant 78 (ENA-78). They induce neutrophil responses via 2 cell-surface receptors, CXCR-1 and CXCR-2. All 3 chemokines bind CXCR-2 with high affinity. Only IL-8 and GCP-2 bind CXCR-1 with high affinity. Hypothesis: The CXC chemokines regulate neutrophil responses differently. Methods: Pretreatment of neutrophils from healthy volunteers with IL-8, GCP-2, or ENA-78; measured IL-8induced migration; and tumor necrosis factor ␣ (TNF-␣)-induced peroxide production. Results: Flow cytometry and radioligand binding data indicate that IL-8, GCP-2, and ENA-78 equivalently reduced CXCR-1 and CXCR-2 cell surface expression by 34% to 54%. All treatments decreased affinity of both receptors 1.5-to 2-fold. However, only IL-8 pretreatment inhibited chemotaxis to 10-nmol/L IL-8 (mean ± SE inhibition, 62% ± 6%). Although IL-8 and GCP-2, but not ENA-78, suppressed TNF-␣-induced oxidant production (mean ± SE inhibition, 42% ± 8% and 40% ± 23%, respectively), only GCP-2 inhibited the oxidative response to complement fragment C5a, and to the bacterial cell wall peptide N-formyl-methionyl-leucylphenylalanine. Conclusions: The CXC chemokines regulate neutrophil proinflammatory functions differently. A thorough understanding of mechanisms for modulating neutrophil responses in inflammation will aid the development of interventions that reduce morbidity and mortality associated with severe trauma and sepsis.

Impaired neutrophil chemotaxis in sepsis associates with GRK expression and inhibition of actin assembly and tyrosine phosphorylation

“…The chemokine receptors CXCR1 and CXCR2 are central for many PMN functions. 29 Although some reports have shown that in vitro treatment with cytokines and/or bacterial products could downregulate CXCR1 and CXCR2 expression on human neutrophils, 23,30 studies with patients with sepsis, confirming our data, showed that expression of CXCR1, the high-affinity receptor for IL-8, were not altered in sepsis. 31,32 Most neutrophil chemoattractants recognize membrane GPCR on the leukocytes and, as a result of receptor activation by the chemoattractant, a complex sequence of signaling events are triggered, inducing profound alterations in cytoskeleton dynamics and activating signaling pathway, allowing neutrophils to develop motile, adhesive, phagocytic, and antimicrobial responses.…”

Inflammatory Chemoreceptor Cross-Talk Suppresses Leukotriene B4 Receptor 1-Mediated Neutrophil Calcium Mobilization and Chemotaxis After Trauma

“…PMN are recruited to sites of bacterial invasion by GPC chemoattractants. There they take part in immune surveillance and the control of infection (35). In vitro, LTs, chemokines, and other chemoattractants can act individually to recruit PMN (14, 15, 36 -39).…”

Immune depression in musculoskeletal trauma

“…IL-8 is a chemokine and belongs to a group of mediators with the ability for leukocyte recruitment and activation at the site of injury [39]. Recently, increases in IL-8 mRNA expression was observed in the early posttraumatic period which preceded down-regulation of the innate immune system, and the expression was correlated to increased mortality [40].…”