Browsing by Author "Seibold, Max A."

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    5-HTP inhibits eosinophilia via intracellular endothelial 5-HTRs; SNPs in 5-HTRs associate with asthmatic lung function
    (Frontiers Media, 2024-05-23) Walker, Matthew T.; Bloodworth, Jeffrey C.; Kountz, Timothy S.; McCarty, Samantha L.; Green, Jeremy E.; Ferrie, Ryan P.; Campbell, Jackson A.; Averill, Samantha H.; Beckman, Kenneth B.; Grammer, Leslie C.; Eng, Celeste; Avila, Pedro C.; Farber, Harold J.; Rodriguez-Cintron, William; Rodriguez-Santana, Jose R.; Serebrisky, Denise; Thyne, Shannon M.; Seibold, Max A.; Burchard, Esteban G.; Kumar, Rajesh; Cook-Mills, Joan M.; Pediatrics, School of Medicine
    Background: Previous research showed that 5-hydroxytryptophan (5HTP), a metabolic precursor of serotonin, reduces allergic lung inflammation by inhibiting eosinophil migration across endothelial monolayers. Objective: It is unknown if serotonin receptors are involved in mediating this 5HTP function or if serotonin receptor (HTR) single nucleotide polymorphisms (SNPs) associate with lung function in humans. Methods: Serotonin receptor subtypes were assessed by qPCR, western blot, confocal microscopy, pharmacological inhibitors and siRNA knockdown. HTR SNPs were assessed in two cohorts. Results: Pharmacological inhibition or siRNA knockdown of the serotonin receptors HTR1A or HTR1B in endothelial cells abrogated the inhibitory effects of 5HTP on eosinophil transendothelial migration. In contrast, eosinophil transendothelial migration was not inhibited by siRNA knockdown of HTR1A or HTR1B in eosinophils. Surprisingly, these HTRs were intracellular in endothelial cells and an extracellular supplementation with serotonin did not inhibit eosinophil transendothelial migration. This is consistent with the inability of serotonin to cross membranes, the lack of selective serotonin reuptake receptors on endothelial cells, and the studies showing minimal impact of selective serotonin reuptake inhibitors on asthma. To extend our HTR studies to humans with asthma, we examined the CHIRAH and GALA cohorts for HTR SNPs that affect HTR function or are associated with behavior disorders. A polygenic index of SNPs in HTRs was associated with lower lung function in asthmatics. Conclusions: Serotonin receptors mediate 5HTP inhibition of transendothelial migration and HTR SNPs associate with lower lung function. These results may serve to aid in design of novel interventions for allergic inflammation.
  • Thumbnail Image
    Item
    CCL5 is a Potential Bridge Between Type-1 and Type-2 Inflammation in Asthma
    (Elsevier, 2023) Gauthier, Marc; Kale, Sagar Laxman; Oriss, Timothy B.; Gorry, Michael; Ramonell, Richard P.; Dalton, Kathryn; Ray, Prabir; Fahy, John V.; Seibold, Max A.; Castro, Mario; Jarjour, Nizar; Gaston, Benjamin; Bleecker, Eugene R.; Meyers, Deborah A.; Moore, Wendy; Hastie, Annette T.; Israel, Elliot; Levy, Bruce D.; Mauger, David; Erzurum, Serpil; Comhair, Suzy A.; Wenzel, Sally E.; Ray, Anuradha; Pediatrics, School of Medicine
    Background: Type 1 (T1) inflammation (marked by IFN-γ expression) is now consistently identified in subsets of asthma cohorts, but how it contributes to disease remains unclear. Objective: We sought to understand the role of CCL5 in asthmatic T1 inflammation and how it interacts with both T1 and type 2 (T2) inflammation. Methods: CCL5, CXCL9, and CXCL10 messenger RNA expression from sputum bulk RNA sequencing, as well as clinical and inflammatory data were obtained from the Severe Asthma Research Program III (SARP III). CCL5 and IFNG expression from bronchoalveolar lavage cell bulk RNA sequencing was obtained from the Immune Mechanisms in Severe Asthma (IMSA) cohort and expression related to previously identified immune cell profiles. The role of CCL5 in tissue-resident memory T-cell (TRM) reactivation was evaluated in a T1high murine severe asthma model. Results: Sputum CCL5 expression strongly correlated with T1 chemokines (P < .001 for CXCL9 and CXCL10), consistent with a role in T1 inflammation. CCL5high participants had greater fractional exhaled nitric oxide (P = .009), blood eosinophils (P < .001), and sputum eosinophils (P = .001) in addition to sputum neutrophils (P = .001). Increased CCL5 bronchoalveolar lavage expression was unique to a previously described T1high/T2variable/lymphocytic patient group in the IMSA cohort, with IFNG trending with worsening lung obstruction only in this group (P = .083). In a murine model, high expression of the CCL5 receptor CCR5 was observed in TRMs and was consistent with a T1 signature. A role for CCL5 in TRM activation was supported by the ability of the CCR5 inhibitor maraviroc to blunt reactivation. Conclusion: CCL5 appears to contribute to TRM-related T1 neutrophilic inflammation in asthma while paradoxically also correlating with T2 inflammation and with sputum eosinophilia.