The required role of endogenously produced lipoxin A4 and annexin-1 for the production of IL-10 and inflammatory hyporesponsiveness in mice.
The appropriate development of an inflammatory response is central for the ability of a host to deal with any infectious insult. However, excessive, misplaced, or uncontrolled inflammation may lead to acute or chronic diseases. The microbiota plays an important role in the control of inflammatory responsiveness. In this study, we investigated the role of lipoxin A4 and annexin-1 for the IL-10-dependent inflammatory hyporesponsiveness observed in germfree mice. Administration of a 15-epi-lipoxin A4 analog or an annexin-1-derived peptide to conventional mice prevented tissue injury, TNF-alpha production, and lethality after intestinal ischemia/reperfusion. This was associated with enhanced IL-10 production. Lipoxin A4 and annexin-1 failed to prevent reperfusion injury in IL-10-deficient mice. In germfree mice, there was enhanced expression of both lipoxin A4 and annexin-1. Blockade of lipoxin A4 synthesis with a 5-lipoxygenase inhibitor or Abs against annexin-1 partially prevented IL-10 production and this was accompanied by partial reversion of inflammatory hyporesponsiveness in germfree mice. Administration of BOC-1, an antagonist of ALX receptors (at which both lipoxin A4 and annexin-1 act), or simultaneous administration of 5-lipoxygenase inhibitor and anti-annexin-1 Abs, was associated with tissue injury, TNF-alpha production, and lethality similar to that found in conventional mice. Thus, our data demonstrate that inflammatory responsiveness is tightly controlled by the presence of the microbiota and that the innate capacity of germfree mice to produce IL-10 is secondary to their endogenous greater ability to produce lipoxin A4 and annexin-1.
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Danielle G
DG
Souza
Caio T
CT
Fagundes
Flavio A
FA
Amaral
Daniel
D
Cisalpino
Lirlândia P
LP
Sousa
Angélica T
AT
Vieira
Vanessa
V
Pinho
Jacques R
JR
Nicoli
Leda Q
LQ
Vieira
Iolanda M
IM
Fierro
Mauro M
MM
Teixeira
D000818:Animals; D017305:Annexin A1 / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000502:physiology*; D005856:Germ-Free Life; D007249:Inflammation / Q000276:immunology* / Q000517:prevention & control; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D007422:Intestines; D044045:Lipoxins / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D010455:Peptides / Q000008:administration & dosage; D015427:Reperfusion Injury / Q000517:prevention & control
D017305:Annexin A1; D044045:Lipoxins; D010455:Peptides; C040527:lipoxin A4; D016753:Interleukin-10