FPR2 deficiency attenuates experimental autoimmune encephalomyelitis (EAE) by modulation of DC function and inhibition of Th17 cell development.

Jong-Hyung Lim

Lim, Jong-Hyung
University of Pennsylvania School of Dental Medicine, Department of Basic and Translational Sciences


Formyl peptide receptor 2 (FPR2) is involved in inflammatory processes, being a receptor for formylated peptides and specific pro-resolving mediators (SPK). FPR2 expression is known to increase in the CNS under inflammatory conditions, however, the function of FPR2 in CNS inflammation e.g. in experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis (MS) is not fully understood. We here aim to study whether FPR2 plays a critical role in the course of EAE using FPR2-knock out mice.


To induce EAE, mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) peptides in complete Freund’s adjuvant, and then injected intraperitoneal with pertussis toxin, and monitored the disease progression on a daily basis until the end of analysis. Leukocytes migrated into spinal cords of EAE mice were assessed by flow cytometric analysis. For Th17 analysis, leukocytes isolated from spinal cords of EAE mice were reactivated with MOG cognate antigen peptides and assessed CD4+IL17+ cells by flow cytometric analysis. Bone marrow-derived dendritic cells (BMDCs) were obtained from mouse femurs and activated with LPS, and DC maturation was assessed by flow cytometric analysis. Cell surface expression of MHC II, CD80, CD86 in matured DCs were evaluated by flow cytometry. mRNA for IL-23p19, IL-6, TNFa and iNOS in matured DCs were analyzed by quantitative PCR. Nitrite levels in matured DC culture supernatants were determined by ELISA. For Th17 cell differentiation co-cultured with DCs, naïve CD4+ T cells isolated from mouse spleen were co-cultured with BMDCs in the presence of TGFb and anti-CD3. The amount of IL-17 in the co-culture supernatants was assessed by ELISA.


FPR2 KO mice displayed a delayed onset of EAE compared to WT littermates, which is associated with decreased frequencies of Th17 cells and dendritic cells (DCs) in the inflamed spinal cords at the early phase of disease. Consistently, in vitro study showed that FPR2 is endogenously expressed in DCs and regulates their function (for instance their maturation and inflammatory cytokine production), and consequently to the DC-mediated activation of Th17 development. Interestingly, we found that FPR2 deficiency induces iNOS expression and nitric oxide production in DCs. As nitric oxide is known to regulate Th17 cell development, our finding in in vitro co-culture conditions suggests that reduced Th17 cells due to FPR2 deficiency in DCs are associated with increased nitric oxide.


FPR2 is seemingly involved in several mechanisms of DC function, including DC maturation, cytokines production by DCs, modulation of nitric oxide activity in DCs, thereby leading to promotion of Th17 differentiation and CNS inflammation.