Production of Chemokines In Vivo in Response to Microbial Stimulation

Abstract

Members of the chemokine gene superfamily are known to play a central role in leukocyte extravasation; however, their involvement in acute inflammation in response to micro-organisms has not yet been well studied. We have therefore investigated the role of murine macrophage-inflammatory protein (muMIP) 1α and muMIP-2 in the inflammatory response mounted against the bacteria Salmonella enteritidis and the Sacchromyces cerevisiae cell wall component, zymosan. Leukocyte extravasation was monitored in murine s.c. air pouches. Both agonists induced accumulation of leukocytes in a dose- and time-dependent manner, with the response peaking after 4 h and declining thereafter. The inflammatory exudate comprised mainly neutrophils; however, an increase in eosinophil accumulation was also observed in response to zymosan. The production of both muMIP-1α and muMIP-2 increased with time in response to both the agonists, although production was more sustained in response to the bacteria. Prior treatment of mice with neutralizing Abs against muMIP-1α or muMIP-2, either alone or in combination, failed to attenuate the accumulation of leukocytes in response to the agonists. In contrast, the anti-muMIP-2 Abs significantly inhibited leukocyte recruitment in response to S. enteritidis in complement-deficient mice. Taken together, these data show that while muMIP-1α and muMIP-2 are produced in response to phagocytosis of micro-organisms in s.c. tissue, under these circumstances components of the complement pathway appear to play a dominant role in the recruitment of neutrophils.

Role of S100A8 and S100A9 in neutrophil recruitment in response to monosodium urate monohydrate crystals in the air‐pouch model of acute gouty arthritis

“…The kinetic profile of the production of these chemokines in the air pouch following MSU crystal injection suggests they could be involved in neutrophil migration in response to MSU crystals. However, individual inactivation with specific blocking antibodies failed to reduce neutrophil accumulation to the pouch, an observation consistent with the results of previous studies, indicating a dominant role for complement, rather than CXCL2 and CCL3, in neutrophil recruitment into the air pouch in response to phagocytic agents such as bacteria (54). Overall, the results of the present study suggest that CXCL2, CXCL1, CCL2, and CCL3 are not individually essential for neutrophil recruitment in response to MSU crystals.…”

“…However, individual inactivation of CXCL1, CXCL2, CCL2, or CCL3 using the same antibodies reduced neutrophil accumulation following TNF␣ and SEA injection (39,40). Nevertheless, the contribution of these chemokines to neutrophil migration differed according to the stimuli because inactivation of CXCL2 and CCL3, either alone or in combination, failed to inhibit leukocyte accumulation in response to bacteria in the air-pouch model (54). In the latter study, components of the complement pathway appeared to override the effect of CXCL2 and CCL3 in the recruitment of neutrophils (54).…”

“…Nevertheless, the contribution of these chemokines to neutrophil migration differed according to the stimuli because inactivation of CXCL2 and CCL3, either alone or in combination, failed to inhibit leukocyte accumulation in response to bacteria in the air-pouch model (54). In the latter study, components of the complement pathway appeared to override the effect of CXCL2 and CCL3 in the recruitment of neutrophils (54). This strongly suggests that chemokine redundancy alone cannot explain the lack of inhibition by specific antibodies, suggesting that other factor(s) are also involved in MSU-induced inflammation.…”

Salmonella enterica serovar Choleraesuis infection of the porcine jejunal Peyer's patch rapidly induces IL-1β and IL-8 expression

“…Caspase-1 enzymatically cleaves IL-1β and IL-18 to their bioactive forms, and IL-1β additionally activates NF-κB-mediated transcription of chemokines (Lee et al, 2004;Monack et al, 2000). The combined secretion of IL-8 (CXCL8), MIP-2 (CXCL2), and MIP-3α (CCL20) induces chemotaxis of neutrophils and dendritic cells to the site of Salmonella invasion (Coates and McColl, 2001;McCormick et al, 1993;Sierro et al, 2001;Zhang et al, 2003).…”

“…Caspase-1 enzymatically cleaves IL-1β and IL-18 to their bioactive forms, and IL-1β additionally activates NF-κB-mediated transcription of chemokines (Lee et al, 2004;Monack et al, 2000). The combined secretion of IL-8 (CXCL8), MIP-2 (CXCL2), and MIP-3α (CCL20) induces chemotaxis of neutrophils and dendritic cells to the site of Salmonella invasion (Coates and McColl, 2001;McCormick et al, 1993;Sierro et al, 2001;Zhang et al, 2003).The early, innate host response to infection is critical for the development of an effective adaptive immune response (Medzhitov and Janeway, 2000). Clarification of the acute molecular and cellular events occurring in response to enteric infection is important in understanding the mechanisms underlying innate immune responses to Salmonella.…”