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P031 STAT6 deficiency alters macrophage polarisation and promotes fibrosis in a murine model of chronic inflammation

P. Salvador*1, D. Ortiz-Masiá1, D. C. Macias-Ceja1, 2, J. Cosín-Roger1, L. Gisbert-Ferrándiz1, C. Hernández2, S. Calatayud1, M. D. Barrachina-Sancho1

1University of Valencia, Valencia, Spain, 2Fisabio Hospital Peset, Valencia, Spain

Background

Intestinal fibrosis, which is caused by excessive extracellular matrix deposition, is a common complication of inflammatory bowel disease. Macrophages assume a wide spectrum of different functional phenotypes (M1, M2a, M2b, and M2c) that differ in the expression of surface proteins, transcription factors, and cytokine production. It is believed that macrophages contribute to all phases of repair, inflammation, proliferation, and remodelling through their progression from M1 to M2c. We have demonstrated that STAT6 (-/-) mice exhibit an impaired M2a polarisation and delayed wound healing in an acute model of colitis. We have hypothesised that these animals are more susceptible to fibrosis development in response to chronic bowel damage.

Methods

WT or STAT6 (-/-) mice were given TNBS (0.5, 0.5, 0.75, 0.75, 1, and 1 mg, intrarectally) or saline weekly, and body weight was recorded daily. Seven days after the last dose, the mice were sacrificed, and the expression of markers of fibrosis (Vimentin, COL1A1,α-SMA, MMP2, FSP-1, and TIMP-1), macrophage markers (CD206, CD16, and CD86), and STAT3 were analysed in colonic tissue by qPCR (results are expressed as fold induction vs vehicle-treated animals).

Results

No significant differences between WT and STAT6 (-/-) mice were detected in body weight loss after TNBS administration. In TNBS-treated mice, STAT6 (-/-) exhibited the following: a) decreased survival (47.6% vs 62.5%); b) increased mucosal expression of markers of fibrosis (Table 1); c) increased expression of M2 markers CD206 (2.2 ± 0.3 vs 0.8 ± 0.1, p < 0.05) and CD16 (2.6 ± 0.3 vs 1.1 ± 0.2, p < 0.01); d) similar levels of the M1 marker CD86 (1.4 ± 0.4 vs 1.1 ± 0.2); and e) increased mRNA expression of STAT3 (1.6 ± 0.1 vs 0.6 ± 0.1, p < 0.01) when compared with their WT counterparts.

Table 1 mRNA expression of markers of fibrosis in WT- and STAT6 (-/-)-TNBS-treated mice. Mean ± s.e.m (n ≥ 3)

Col1A1Vimentinα-SMAMMP2FSP-1TIMP1
WT0.9 ± 0.10.7 ± 0.10.5 ± 0.10.6 ± 0.10.7 ± 0.21.2 ± 0.6
STAT6 (-/-)6.6 ± 2.2*2.2 ± 0.3**2.4 ± 0.1***2.7 ± 3.4**3.1 ± 0.93.4 ± 1.0

Conclusion

Conclusion: STAT6 deficiency promotes fibrosis in TNBS-treated mice, which is associated with the up regulation of STAT3 and polarisation of macrophages towards an M2c phenotype.