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1.
The endocannabinoid system in asthma patients and the effect of cannabinoids in the modulation of inflammatory response
Carina Esteves Pinto Kozmus, 2021, doctoral dissertation

Abstract: Asthma is a chronic inflammatory condition characterised by intermittent and reversible airflow obstruction caused by inflammation, bronchospasm, and increased airway secretions. Questions about the endocannabinoid system’s function in asthma pathogenesis have arisen as evidence grows, demonstrating it is a native modulator of immune functions. The main goal of this study was to genetically characterise the endocannabinoid system in naive asthma patients and determine if there is a relationship between endogenous cannabinoids and their inflammatory response. We studied a case-control cohort of 353 patients with mild/moderate persistent asthma and 276controls. The mRNA expression levels of the selected genes were quantified in peripheral blood mononuclear cells (PBMCs) and N-acylethanolamines (NAEs) quantified from plasma samples. Our results revealed that the genes for CB1 (CNR1) andCB2 (CNR2), along with genes for the enzymes NAPE-PLD (NAPEPLD), Abhd4(ABHD4) and MAGL (MGLL) were up-regulated in asthma patients and associated with their clinical and inflammatory condition. In addition, two of the genotyped polymorphisms located in the CNR2 gene were also associated with worse clinical symptoms. Palmitoylethanolamide (PEA) levels were lower and significantly different between allergic asthma patients and the control group and associated with worse clinical symptoms. Furthermore, our findings indicate that asthma patients with highCNR1mRNA expression levels at the time of diagnosis, treated with LTA, have better treatment response, while asthma patients with highCNR1mRNA expression levels, treated with ICS, had worse treatment response. Long-term ICS or LTRA therapy reduced mRNA expression ofCNR1together withIL4andIL5.It is evident from these findings that the endocannabinoid system plays a role in asthma, but it is not possible to determine whether this up-regulation is a cause or a result of the condition. Nonetheless, our findings add to a better understanding of the endocannabinoid system’s significance in asthma pathogenesis.
Keywords: Asthma, Endocannabinoid system, Cannabinoids, Inflammation, Molecular genetics
Published in DKUM: 18.03.2024; Views: 77; Downloads: 5
.pdf Full text (10,46 MB)

2.
Cleavage-mediated regulation of Myd88 signaling by inflammasome-activated caspase-1
Monika Avbelj, Iva Hafner Bratkovič, Duško Lainšček, Mateja Manček Keber, Tina Tinkara Peternelj, Gabriela Panter, Steven P. Treon, Boris Gole, Uroš Potočnik, Roman Jerala, 2022, original scientific article

Abstract: Coordination among multiple signaling pathways ensures an appropriate immune response, where a signaling pathway may impair or augment another signaling pathway. Here, we report a negative feedback regulation of signaling through the key innate immune mediator MyD88 by inflammasome-activated caspase-1. NLRP3 inflammasome activation impaired agonist- or infection-induced TLR signaling and cytokine production through the proteolytic cleavage of MyD88 by caspase-1. Site-specific mutagenesis was used to identify caspase-1 cleavage site within MyD88 intermediary segment. Different cleavage site location within MyD88 defined the functional consequences of MyD88 cleavage between mouse and human cells. LPS/monosodium urate–induced mouse inflammation model corroborated the physiological role of this mechanism of regulation, that could be reversed by chemical inhibition of NLRP3. While Toll/interleukin-1 receptor (TIR) domain released by MyD88 cleavage additionally contributed to the inhibition of signaling, Waldenström’s macroglobulinemia associated MyD88L265P mutation is able to evade the caspase-1-mediated inhibition of MyD88 signaling through the ability of its TIRL265P domain to recruit full length MyD88 and facilitate signaling. The characterization of this mechanism reveals an additional layer of innate immunity regulation.
Keywords: Myeloid differentiation factor 88, Myd88, caspase-1, inflammasomes, regulation, innate immunity, inflammation
Published in DKUM: 16.08.2023; Views: 369; Downloads: 22
.pdf Full text (12,17 MB)
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