Up-regulation of Annexin-A1 and lipoxin A(4) in individuals with ulcerative colitis may promote mucosal homeostasis.
BACKGROUND
One of the characteristics of an active episode of ulcerative colitis (UC) is the intense mucosal infiltration of leukocytes. The pro-resolution mediators Annexin-A1 (AnxA1) and lipoxin A(4) (LXA(4)) exert counter-regulatory effects on leukocyte recruitment, however to date, the dual/cumulative effects of these formyl peptide receptor-2 (FPR2/ALX) agonists in the context of human intestinal diseases are unclear. To define the contribution of these mediators, we measured their expression in biopsies from individuals with UC.


METHODS
Colonic mucosal biopsies were collected from two broad patient groups: healthy volunteers without ('Ctrl' n  = 20) or with a prior history of UC ('hx of UC' n = 5); individuals with UC experiencing active disease ('active' n = 8), or in medically-induced remission ('remission' n = 16). We assessed the mucosal expression of LXA(4), AnxA1, and the FPR2/ALX receptor in each patient group using a combination of fluorescence microscopy, biochemical and molecular analyses.


RESULTS
Mucosal expression of LXA(4) was elevated exclusively in biopsies from individuals in remission (3-fold, P<0.05 vs. Ctrl). Moreover, in this same group we observed an upregulation of AnxA1 protein expression (2.5-fold increase vs. Ctrl, P<.01), concurrent with an increased level of macrophage infiltration, and an elevation in FPR2/ALX mRNA (7-fold increase vs. Ctrl, P<.05). Importantly, AnxA1 expression was not limited to cells infiltrating the lamina propria but was also detected in epithelial cells lining the intestinal crypts.


CONCLUSIONS
Our results demonstrate a specific up-regulation of this pro-resolution circuit in individuals in remission from UC, and suggest a significant role for LXA(4) and AnxA1 in promoting mucosal homeostasis.
Hospital for Sick Children, Research Institute, Toronto, Ontario, Canada. linda.vong@sickkids.ca
Linda
L
Vong
Jose G P
JG
Ferraz
Neil
N
Dufton
Remo
R
Panaccione
Paul L
PL
Beck
Philip M
PM
Sherman
Mauro
M
Perretti
John L
JL
Wallace
D000328:Adult; D017305:Annexin A1 / Q000235:genetics / Q000378:metabolism*; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006098:Granulocytes / Q000276:immunology / Q000473:pathology; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D044045:Lipoxins / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D044042:Receptors, Formyl Peptide / Q000235:genetics / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D017305:Annexin A1; D016207:Cytokines; C105101:FPR2 protein, human; D018836:Inflammation Mediators; D044045:Lipoxins; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C040527:lipoxin A4; D051546:Cyclooxygenase 2