Posttraumatic stress disorder (PTSD) is a debilitating mental health condition afflicting 8% of the population. Better understanding of contributory neurobiological mechanisms will lead to effective treatments, improving quality of life for patients. Given that not all trauma-exposed individuals develop PTSD, identification of pre- trauma factors modulating posttraumatic outcomes is important. Recent clinical evidence supports a strong link between chronic inflammatory conditions and susceptibility to PTSD. A particularly strong link has been reported between severe asthma and PTSD prevalence and severity, suggesting that immune mediators associated with the development of severe asthma may impact posttraumatic outcomes. In a novel mouse model of severe house dust mite (HDM)-evoked airway hypersensitivity in which Th17/IL17A play a central role, we observed significant deficits in fear extinction and altered neuronal activity in fear regulatory prefrontal and amygdala areas, an rapid increase in brain IL17+ve cells, and microglial alterations in BBB-devoid circumventricular organ (CVO), subfornical organ (SFO). Supported by findings of elevated Th17/IL17A in both individuals with severe asthma, and PTSD subjects, our data raise the intriguing possibility that severe asthma-associated IL17A production may induce neuroimmune changes and worsen PTSD-relevant behaviors following trauma. Using a conjunct HDM- traumatic stress model, we plan to test our hypothesis by pursuing two aims:
Aim 1 will test the hypothesis that pro-inflammatory IL17A production characteristic of severe asthma is necessary for HDM-induced exacerbation of PTSD-relevant behaviors (fear, startle, anxiety) following single prolonged stress (SPS). Transgenic models of asthma severity targeting IL-17A-signaling pathways (Il17ra-/-), or Th17-associated immune responses (Il23a- /-) will be used to determine if mice lacking the ability to respond to IL-17A, or differentiation into Th17 cells display abrogated development of PTSD-relevant behaviors after HDM exposure.
Aim 2 will determine the temporal trajectory of HDM-evoked neuroimmune alterations. Immune cell recruitment, pro-inflammatory cytokine levels, microglial activation and neural activity in CVOs and fear/stress regulatory brain areas at various times post-allergen/pre-trauma, and post-trauma will be examined. Our data will identify potential mechanisms by which pre-trauma inflammation associated with airway hypersensitivity can regulate posttraumatic stress outcomes. However, while our model explores the role of these factors in severe asthma, similar mechanisms could be reasonably argued to drive the link between PTSD and other inflammatory conditions, (rheumatoid arthritis, lupus, IBD) many of which are also associated with elevated pro-inflammatory cytokine production. Thus, elucidation of a direct link between IL-17A and PTSD would have broadly applicable implications for understanding PTSD risk and pathophysiology, as well as identify alternative therapeutics.
PTSD is a trauma-evoked, debilitating condition afflicting 8% of the general population and about 22% of combat veterans annually. Strong clinical evidence supports an association of severe asthma with PTSD prevalence and risk. Using novel genetic mice models, this R21 investigates asthma-linked inflammatory mechanisms in driving posttraumatic behavior and physiology.