Abstract
Deficient innate and adaptive immune responses cause newborn mammals to be more susceptible to bacterial infections than adult individuals. Toll-like receptors (TLRs) are known to play a pivotal role in bacterial recognition and subsequent immune responses. Several studies have indicated that activation of certain TLRs, in particular TLR-2, can result in suppression of inflammatory pathology. In this study, we isolated peripheral blood mononuclear cells (PBMCs) from adult and newborn horses to investigate the influence of TLR-2 activation on the inflammatory response mediated by TLR-4. Data were analysed in a Bayesian hierarchical linear regression model, accounting for variation between horses. In general, cytokine responses were lower in PBMCs derived from foals compared with PBMCs from adult horses. Whereas in foal PBMCs expression of TLR-2, TLR-4, and TLR-9 was not influenced by separate and concomitant TLR-2 and TLR-4 activation, in adult horse PBMCs, both TLR ligands caused significant up-regulation of TLR-2 and down-regulation of TLR-9. Moreover, in adult horse PBMCs, interleukin-10 protein production and mRNA expression increased significantly following concomitant TLR-2 and TLR-4 activation (compared with sole TLR-4 activation). In foal PBMCs, this effect was not observed. In both adult and foal PBMCs, the lipopolysaccharide-induced pro-inflammatory response was not influenced by pre-incubation and co-stimulation with the specific TLR-2 ligand Pam3-Cys-Ser-Lys4. This indicates that the published data on other species cannot be translated directly to the horse, and stresses the necessity to confirm results obtained in other species in target animals. Future research should aim to identify other methods or substances that enhance TLR functionality and bacterial defence in foals, thereby lowering susceptibility to life-threatening infections during the first period of life.
Highlights
Due to deficits in both innate and adaptive immune responses, newborn mammals display increased susceptibility to bacterial infections compared with adult individuals [1]
We investigated protein levels of tumour necrosis factor-a (TNF-a) and IL-10, and mRNA expression levels of TNF-a and IL-6 (Th1-related cytokines), IL-10, and Toll-like receptors (TLRs)-2, TLR-4, and TLR-9 (TLRs involved in bacterial recognition, for which the genetic sequence is known in the horse)
Cytokine production ELISA results for equine TNF-a and IL-10 are illustrated in figure 1
Summary
Due to deficits in both innate and adaptive immune responses, newborn mammals display increased susceptibility to bacterial infections compared with adult individuals [1]. In ex vivo foal models, basal levels of Th1-related cytokines such as interferon-c (IFN-c), tumour necrosis factor-a (TNF-a), and interleukin-6 (IL-6) have been shown to be decreased compared with older individuals [3,4,5]. Basal and stimulus-induced levels of Th2related cytokines such as IL-8, IL-12, and IL-23 have been shown to be comparable in foals and older individuals [3,4]. In response to the specific pathogen Rhodococcus equi, no Th1deficits have been found in neonatal foals [3,6,7] the basal and stimulus-induced cytokine expression in neonatal foals appears to be selectively impaired. In human infants, who are biased towards Th2 responses as well, mature Th1 responses have been documented in response to Group B Streptococci [1]
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