Reversal of the detrimental effects of social isolation on ischemic cerebral injury and stroke-associated pneumonia by inhibiting small intestinal gamma delta T-cell migration into the brain and lung

Social isolation (ISO) is associated with an increased risk and poor outcomes of ischemic stroke. However, the roles and mechanisms of ISO in stroke-associated pneumonia (SAP) remain unclear. Adult male mice were single- or pair-housed with an ovariectomized female mouse and then subjected to transient middle cerebral artery occlusion. Isolated mice were treated with the natriuretic peptide receptor A antagonist A71915 or anti-gamma-delta (gamma delta) TCR monoclonal antibody, whereas pair-housed mice were treated with recombinant human atrial natriuretic peptide (rhANP). Subdiaphragmatic vagotomy (SDV) was performed 14 days before single- or pair-housed conditions. We found that ISO significantly worsened brain and lung injuries relative to pair housing, which was partially mediated by elevated interleukin (IL)-17A levels and the migration of small intestine-derived inflammatory gamma delta T-cells into the brain and lung. However, rhANP treatment or SDV could ameliorate ISO-exacerbated post-stroke brain and lung damage by reducing IL-17A levels and inhibiting the migration of inflammatory gamma delta T-cells into the brain and lung. Our results suggest that rhANP mitigated ISO-induced exacerbation of SAP and ischemic cerebral injury by inhibiting small intestine-derived gamma delta T-cell migration into the lung and brain, which could be mediated by the subdiaphragmatic vagus nerve.