University of Pittsburgh/UPMC Children's Hospital of Pittsburgh Pittsburgh, PA, United States
Catherine Poholek1 and Mandy McGeachy2, 1UPM Children's Hospital of Pittsburgh/University of Pittsburgh, Pittsburgh, PA, 2University of Pittsburgh, Pittsburgh, PA
Background/Purpose: Autoimmune disease (AID) resulting from a dysregulated immune response is associated with substantial morbidity and mortality, largely driven by cardiovascular disease (CVD)/atherosclerosis and dyslipidemia. Even in patients with similar CVD risk factors, those with AID have increased rates of CVD. Despite the well-recognized link between inflammation and dyslipidemia, the driving mechanisms remain poorly understood.
Initiation of immune responses occurs in lymph nodes (LNs), which are highly organized structures that facilitate coordinated cell-cell interactions. Stromal cells including fibroblastic reticular cells (FRCs) establish this structure and facilitate optimal lymphocyte responses and antibody production. IL-17, which is produced by Th17 cells, acts on FRCs to promote proliferation and metabolic fitness during inflammation, and IL-17 signaling on FRCs is required for FRC expansion and optimal germinal center formation. IL-17 also plays a pathogenic role in several AIDs. We now show that IL-17 signaling on FRCs regulates the expression of apolipoprotein E (apoE) during the immune response. ApoE is a lipid binding protein that mediates chylomicron and lipid clearance from circulation and regulates cholesterol efflux from cells. In this study we advance the understanding of the mechanistic link between inflammation and lipid homeostasis, which may yield novel therapeutic targets in AID-associated dyslipidemia and CVD.
Methods: Mouse strains with targeted deletion of IL-17 receptor or ApoE in FRCs (FRCΔIl17ra or FRCΔApoE) were generated by crossing CCL19-Cre mice with Il17rafl/fl or ApoEfl/fl mice; CCL19-Cre negative littermates were used as controls (FRCCtrl). We infected mice by oral gavage with the murine intestinal pathogen Citrobacter rodentium to induce colitis or immunized subcutaneously with myelin oligodendrocyte glycoprotein (MOG) peptide and Complete Freud's Adjuvant (CFA) to induce autoimmune CNS disease. Serum, draining LNs and colons from infected or immunized and naïve mice were analyzed using quantitative PCR, flow cytometry, and ELISA.
Results: Following immunization with MOG/CFA, FRCs downregulate the expression of ApoE; however, in FRCΔIl17ra mice, this downregulation is greatly abrogated. Expression of ApoE is reduced by 2-fold in LNs from naïve FRCΔApoE mice compared to FRCCtrl mice, suggesting FRCs are a major source of ApoE in LNs. In mesenteric LNs from naïve FRCΔApoE mice there is increased expression of pro-inflammatory cytokines, suggesting a state of chronic inflammation. After infection with C. rodentium, FRCΔApoE mice have significantly shortened colons compared to FRCCtrl mice, corresponding to increased intestinal inflammation. In line with this, colons from FRCΔApoE infected mice have increased expression of pro-inflammatory cytokines. Surprisingly, there is a reduction in T follicular helper (Tfh) and B cells in the mLNs of infected FRCΔApoE mice.
Conclusion: Together, these data suggest that apoE expression by FRCs acts to finetune the immune response by promoting favorable induction of Tfh and B cells while limiting the induction of tissue-damaging inflammatory cells.