Abstract

It is a fact that cigarette smoke (CS) has negative effects on patients with Crohn's disease (CD), whereas CS seems to provide protection to patients with Ulcerative Colitis (UC). The mechanism of how CS ingredients or nicotine modulate inflammatory phenotypic response in IBD subsets remained unclear. Unlike UC, CD has been associated with genetic disposition, immuno-dysregulation and infection by pathogens mainly Mycobacterium avium paratuberculosis (MAP). In this study, we investigated the cellular and molecular effects of pure nicotine and tobacco extracts from HLE-nicotine rich-plant and LAMD-nicotine less-plant in infected macrophages. Unlike LAMD extracts, Nicotine (4ug/mL) and HLE extracts (0.18%) significantly favored M2 polarization and phenotypic response. While macrophages infected with MAP or treated with LPS promoted pro-inflammatory response, treatment of infected macrophages with nicotine/HLE extracts further elevated pro-inflammatory response, and enhanced MAP burden. Pre-conditioning macrophages with nicotine or blocking alpha-7nAChR with antagonist reversed the effect of nicotine in infected macrophages. We demonstrated that MAP infection in macrophages was mediated through TLR2/MyD88 signaling; blocking TLR2 and TLR4 with antagonists significantly reduced the inflammatory effect of MAP and LPS. Interestingly, nicotine in infected macrophages significantly downregulated TLR2/TLR4 expression, activated MyD88, and increased expression of pro-inflammatory cytokines. Surprisingly, dual treatment of MAP-infected macrophages with MyD88 antagonist and nicotine absolutely impaired immune response during infection. The data shows a role for TLR2/MyD88 signaling in elevated inflammatory response during infection in CD smokers. Overall, we conclude that in absence of infection in UC, nicotine activates the cholinergic anti-inflammatory pathway through alpha-7nAChRs. However, in CD smokers with MAP infection, nicotine action is mediated through TLR2/MyD88 signaling leading to significant inflammatory response. The study is the first to unmask the mechanism involved in the contradictory effect of CS in IBD populations.

Notes

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Graduation Date

2020

Semester

Fall

Advisor

Naser, Saleh

Degree

Doctor of Philosophy (Ph.D.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Degree Program

Biomedical Sciences

Format

application/pdf

Identifier

CFE0008766;DP0025497

URL

https://purls.library.ucf.edu/go/DP0025497

Language

English

Release Date

6-15-2021

Length of Campus-only Access

None

Access Status

Doctoral Dissertation (Open Access)

Location

College of Medicine

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