The Required Role of Endogenously Produced Lipoxin A4 and Annexin-1 for the Production of IL-10 and Inflammatory Hyporesponsiveness in Mice

Abstract

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-α 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-α 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.

Ligand-specific conformational change of the G-protein–coupled receptor ALX/FPR2 determines proresolving functional responses

“…In vivo injections of anti-inflammatory doses of AnxA1 (26) led to IL-10 production in an ALXdependent manner, as demonstrated using a mouse colony deficient in the ortholog for the human receptor (4). Some evidence for a link between AnxA1 and IL-10 has been advanced in the literature using macrophages (27) and in models of gut injury (28). Our data provide molecular support to this pathway, linking the protein AnxA1-a master regulator of resolution (29)-and the cytokine IL-10 to ALX homodimerization.…”

Protectin D1 n-3 DPA and resolvin D5 n-3 DPA are effectors of intestinal protection

“…The clinical efficacy of anti-TNF therapy in IBD (3) supports this mechanism. Of interest, both PD1 n-3 DPA and RvD5 n-3 DPA did not regulate colonic levels of IL-10, setting these mediators apart from LXA 4 (28) or other proresolving mediators, like Annexin-A1 (29,30) and α-melanocyte stimulating hormone (31). To substantiate the physio-pathological impact of this new pathway, it was important to observe that inhibition of the enzyme responsible for conversion of DPA to DHA led to increased tissue levels of n-3 DPA-derived SPM, an effect linked to a reduction in systemic eicosanoid levels during I/R injury, supporting the host protective actions of these molecules.…”

The Role and Effects of Glucocorticoid-Induced Leucine Zipper in the Context of Inflammation Resolution

“…Finally, we investigated whether inhibiting AnxA1 in GILZ 2/2 mice could affect the phenotype of these mice. By using an AnxA1 neutralizing Ab previously used in other studies (15,22), we showed that mice in which AnxA1 was neutralized were refractory to resolution induced by Dex (Fig. 6C), indicating that by preventing the compensatory effects of AnxA1, GILZ 2/2 mice lost the ability to resolve inflammation in response to GC treatment.…”

“…To prevent the action of AnxA1 induced by Dex, mice were treated with anti-AnxA1 antiserum (0.1 ml hyperimmune serum diluted in 100 ml PBS/mouse, i.p.) (22). Nonimmune goat serum was used as control.…”