Colonization with Pseudomonas aeruginosa (PA), the most common pathogen isolated mainly in patients with cystic fibrosis, is particularly difficult to eradicate and is associated with acceleration of decline in lung function and with poorer prognosis. PA LPS is recognized by Toll-like receptors-4 (TLR4) and has been shown to induce lung inflammation in vivo. In addition, regulation of this process is essential for proper pathogen clearance and to prevent excessive inflammatory response resulting in tissue damage. One potential regulator of these process is the peroxisome proliferator-activated receptors (PPARs), and in particular PPARα. Thus, the purpose of the present study was to evaluate the effects of the absence of TLR4 and PPARα receptors in the pulmonary innate immunity response to PA and in the consequent inflammatory response and in the activation of the macromolecular complex of the NLRP3 inflammosome.
To evaluate the involvement of TLR4 and PPARα in a PA infection, we used TLR4 KO and PPARα KO mice that received an intratracheal (i.t.) administration of 50 μL of PA strain (106 CFU), thus evaluating if these mice were profoundly susceptible to PA compared with WT mice.
The results of the present study showed that administration of PA worsened the pathophysiology of PA lung disease in TLR4 and PPARα KO mice compared with WT mice.
The present study demonstrated that TLR4 and PPARα receptors would mediate the earliest control of bacterial replication as well as proinflammatory responses to PA infections, and in particular that PPARα receptors are needed to prevent an excessive inflammatory response, as in the control of the inflammasome complex NLP3 activation.
*Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
†Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri
Address reprint requests to Rosanna Di Paola, PhD, University of Messina, Viale Ferdinando Stagno D’Alcontres, no. 31, Messina 98166, Italy; E-mail: firstname.lastname@example.org
Received 21 December, 2017
Revised 23 January, 2018
Accepted 5 March, 2018
Authors’ contributions: EG participated in research design, carried out the in vivo experiments analysis and drafted the manuscript. RF participated in research design, carried out the in vivo experiments and revised the manuscript. RD performed the western blot analysis, and carried out the ELISA assay. CB and GG provided the bacterial inoculum and revised the manuscript. GM analyzed the data and revised the manuscript. SC and RDP contributed to writing of the manuscript and designing the experiments. All authors read and approved the final manuscript.
This study was authorized by the University of Messina Review Board for the care of animals. Animal care followed Italian (D.M.116192) and EEC (O.J. of E.C. L 358/1 12/18/1986) regulations on protection of animals used for experimental and scientific purposes.
The datasets generated and/or analyzed during the present study are not publicly available due) but are available from the corresponding author on reasonable request
The authors report no conflicts of interest statements.