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Systemic and intestinal levels of factor XIII-A: the impact of inflammation on expression in macrophage subtypes

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Abstract

Background

Subunit A of coagulation factor XIII (FXIII-A) is important for clot stability and acts in the subsequent wound healing process. Loss of plasma FXIII-A has been reported after surgery, sepsis, and inflammatory conditions. In the intestinal mucosa, FXIII-A is expressed by macrophages and cellular FXIII-A has been associated with phagocytosis and migration of macrophages. The objective was to evaluate the consequences of intestinal inflammation on resident mucosal macrophages, focusing on the level and distribution of FXIII-A.

Methods

Plasma and colonic biopsies were collected from 67 patients with ulcerative colitis and controls. Intestinal samples were stained using immunohistochemistry for FXIII-A and macrophages (CD68, CD163 and iNOS). In situ hybridization were used to assess the intestinal expression of FXIII-A. FXIII-A antigen and activity levels were measured in plasma.

Results

Increased infiltration of CD68 positive macrophages in the inflamed mucosa coincided with increased extracellular deposited FXIII-A and decreased expression and intracellular protein levels of FXIII-A. A decreased proportion of FXIII-A/CD68/CD163 triple-positive macrophages was observed in inflamed mucosa, indicating a reduction of the M2 phenotype with consequent loss of FXIII-A. No induction of iNOS positive macrophages was observed. Stimulation of naïve monocytes with physiological concentrations of pro-inflammatory mediators negatively affected the expression of FXIII-A. Measurements in plasma confirmed the loss of both FXIII antigen and activity during active disease.

Conclusions

Intestinal inflammation in UC induces loss of M2 macrophages with subsequent loss of FXIII-A synthesis. The loss of cellular FXIII-A may impact migration and phagocytosis, and hence limit pathogen eradication in UC.

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Acknowledgments

The authors would like to thank staff pathologist Lene Buhl Riis for the histopathological evaluation of biopsy specimens and Thomas Nygaard Jensen for plasma measurements of FXIII.

Authorship contributions

C Soendergaard recruited patients and performed the experiments. Measurements of plasma FXIII were conducted by H. Pelzer. The manuscript was drafted by C. Soendergaard, with intellectual input provided by O.H. Nielsen, J.B. Seidelin and P.H. Kvist, who contributed to the drafting and finalization. All authors approved the final manuscript.

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Authors and Affiliations

  1. Department of Gastroenterology 54O3, Medical Section, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark

    Christoffer Soendergaard, Jakob Benedict Seidelin & Ole Haagen Nielsen

  2. Department of Histology and Bioimaging, Novo Nordisk A/S, Maaloev, Denmark

    Christoffer Soendergaard & Peter Helding Kvist

  3. Department of Research Bioanalysis, Novo Nordisk A/S, Maaloev, Denmark

    Hermann Pelzer

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  1. Christoffer Soendergaard
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Correspondence to Christoffer Soendergaard.

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Conflict of interest

C. Soendergaard, P.H. Kvist and H. Pelzer are employed by Novo Nordisk A/S, Denmark. All authors declare that they have no conflicts of interest to disclose. The study received no external funding.

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Soendergaard, C., Kvist, P.H., Seidelin, J.B. et al. Systemic and intestinal levels of factor XIII-A: the impact of inflammation on expression in macrophage subtypes. J Gastroenterol 51, 796–807 (2016). https://doi.org/10.1007/s00535-015-1152-2

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  • DOI: https://doi.org/10.1007/s00535-015-1152-2

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