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.