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

Abstract

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 (γδ) 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 γδ 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 γδ 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 γδ T-cell migration into the lung and brain, which could be mediated by the subdiaphragmatic vagus nerve.

Gut-derived memory γδT17 cells exacerbate sepsis-induced acute lung injury

“…For in vivo tracing of intestinal immune cells, photoconversion was performed, as previously described 41 . Brie y, after completion of CLP or sham surgery, the small intestine of Kaede-transgenic mice were exposed to a 405-nm laser for a duration of 10 min, while ensuring the surrounding tissue was shielded from light using aluminum foil.…”

“…Cell suspensions from lung, small intestine, mesenteric lymph nodes (MLNs), blood and spleen were prepared as previously reported 41 . Cells were blocked with 5 ng µl -1 of anti-CD16/CD32 antibody for 10 min at 4 ℃ and stained with the appropriate antibodies.…”

“…Single cell suspensions from small intestines were prepared as previously reported 41 . In brief, the small intestines were carefully cleaned and opened longitudinally, washed with PBS, cut into 1.0-1.5 cm pieces and incubated in 20 ml of HBSS/10 mM HEPES, 8% FBS, 4 mM EDTA, and 0.5 mM dithiothreitol at 37 ℃ with constant agitation for 15 minutes twice.…”

Emerging role of the host microbiome in neuropsychiatric disorders: overview and future directions

“…Furthermore, antibiotic-induced microbiome depletion could reduce acute lung injury after lipopolysaccharide administration [ 136 ]. Another recent study demonstrated that small intestinal γδ T-cell migration into the lung and brain plays a role in stroke-associated pneumonia in mice [ 56 ]. Given the emerging recognition of the lung–brain axis [ 135 , 137 , 138 ], it becomes increasingly compelling to explore whether the lung microbiota plays a role in the development and progression of neuropsychiatric disorders.…”