Role of lysyl oxidase-like-4 in modulating the macrophage transition in ulcerative colitis

Project: Research project

Project Details


Ulcerative colitis (UC) is a chronic relapsing intestinal disorder that characterized by mucosal inflammation as a result of robust pro-inflammatory cytokine production. Current therapies targeted on dampening inflammation, yet failed to achieve complete remission in most UC patients due to lack of understanding on the mechanism underlying the perpetuated intestinal inflammation. Growing evidences have pointed that failure in functional transition of macrophages towards anti-inflammatory phenotype results in dysregulated pro-inflammatory macrophages accumulation and loss of mucosal tolerance that supports inflammation-associated UC progression.

We and others identified the impaired tolerogenic role of lysyl oxidase (LOX) and its family member, LOXL4 in macrophages apart from its role in extracellular matrix remodelling. Our pilot study observed that the mRNA and protein expression of LOXL4 was particularly up-regulated in the inflamed intestinal tissues of UC patients. This increase can be replicated in chronic colitis model induced by dextran sodium sulphate (DSS) in C57BL/6 mice. Furthermore, LOXL4 blockade reduced the disease severity and decreased the extent of intestinal inflammation in the chronic DSS-induced colitis mice and spontaneous T cell transferred Rag1-/- mice.

LOXL4 was highly expressed in colonic macrophages under pathological state. High expression of LOXL4 was accounted for the pro-inflammatory TNFα and Il1 while suppressive anti-inflammatory il10 genes expression in macrophages. More importantly, adoptive transfer of LPS-induced pro-inflammatory BMDM to the anti-LOXL4-treated Rag1-/- colitis mice exacerbated the mice susceptibility to colitis and enhanced colonic pro-inflammatory TNFα and IL1β genes expression. Proteomic analysis revealed that LOXL4 primarily regulated the fatty acid β-oxidation (FAO)-associated cellular events in colonic macrophages. Further pathway analysis using phosphorylation protein array showed that LOXL4 particularly reduced AMPKα phosphorylation in macrophages. AMPKα activation however restored the FAO-regulated anti-inflammatory genes expression in macrophages with LOXL4 overexpression.

Based on our preliminary observation, we hypothesize that LOXL4 expression contributes to UC progression through inducing impairment of the anti-inflammatory phenotype transition in colonic macrophages. We aim to
(1) functionally characterize the role of LOXL4 during colitis progression;
(2) delineate the mechanisms of LOXL4 in regulating macrophage phenotypic transition;
(3) determine the therapeutic potential of targeting LOXL4 in colitis mice.
Successful demonstration of this project will facilitate the development of novel therapeutic insight for UC management.
Effective start/end date1/01/2431/12/26


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