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Production of chemokines in vivo in response to microbial stimulation
1Chemokine Biology Laboratory, Department of Molecular BioSciences, University of Adelaide, Adelaide, South Australia, Australia.
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) 1alpha 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-1alpha 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-1alpha 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-1alpha 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.
Insights
Murine macrophage-inflammatory proteins (muMIP) 1alpha and muMIP-2 are produced during microbial infections. However, complement pathways, not these chemokines, primarily drive neutrophil recruitment in acute inflammation.
Area of Science:
- Immunology
- Inflammation Research
Background:
- Chemokines are key in leukocyte extravasation.
- The role of murine macrophage-inflammatory protein (muMIP) 1alpha and muMIP-2 in acute microbial inflammation requires further study.
Purpose of the Study:
- To investigate the role of muMIP-1alpha and muMIP-2 in inflammatory responses to Salmonella enteritidis and zymosan.
- To determine the contribution of these chemokines to leukocyte recruitment in vivo.
Main Methods:
- Leukocyte extravasation was monitored in murine s.c. air pouches following administration of agonists.
- Production of muMIP-1alpha and muMIP-2 was measured over time.
- Neutralizing antibodies against muMIP-1alpha and muMIP-2 were used in wild-type and complement-deficient mice.
Main Results:
- Both muMIP-1alpha and muMIP-2 induced dose- and time-dependent leukocyte accumulation, primarily neutrophils.
- Microbial challenge increased muMIP production, with sustained levels against bacteria.
- Neutralizing antibodies failed to inhibit leukocyte accumulation in wild-type mice, but anti-muMIP-2 antibodies reduced neutrophil recruitment in complement-deficient mice.
Conclusions:
- muMIP-1alpha and muMIP-2 are produced during microbial phagocytosis in subcutaneous tissue.
- Complement pathway components play a dominant role in neutrophil recruitment during acute microbial inflammation, rather than muMIP-1alpha and muMIP-2 alone.