Salmonella Infection Enhances Erythropoietin Production by the Kidney and Liver, Which Correlates with Elevated Bacterial Burdens

Abstract

Salmonella infection profoundly affects host erythroid development, but the mechanisms responsible for this effect remain poorly understood. We monitored the impact of Salmonella infection on erythroid development and found that systemic infection induced anemia, splenomegaly, elevated erythropoietin (EPO) levels, and extramedullary erythropoiesis in a process independent of Salmonella pathogenicity island 2 (SPI2) or flagellin. The circulating EPO level was also constitutively higher in mice lacking the expression of signal-regulatory protein ␣ (SIRP␣). The expression level of EPO mRNA was elevated in the kidney and liver but not increased in the spleens of infected mice despite the presence of extramedullary erythropoiesis in this tissue. In contrast to data from a previous report, mice lacking EPO receptor (EPOR) expression on nonerythroid cells (EPOR rescued) had bacterial loads similar to those of wild-type mice following Salmonella infection. Indeed, treatment to reduce splenic erythroblasts and mature red blood cells correlated with elevated bacterial burdens, implying that extramedullary erythropoiesis benefits the host. Together, these findings emphasize the profound effect of Salmonella infection on erythroid development and suggest that the modulation of erythroid development has both positive and negative consequences for host immunity.

CD71+VISTA+ erythroid cells promote the development and function of regulatory T cells through TGF-β

“…Overall, our previous studies have revealed that neonatal vulnerability to infection results from the temporary existence of immunosuppressive CD71 + erythroid cells. In agreement, a recent study has shown a marked expansion of erythroid precursors (CD71 + TER119 + ) in murine spleens following Salmonella infection and demonstrated that presence of these cells was associated with enhanced bacterial persistence [9]. More recently, the immunomodulatory properties of CD71 + erythroid cells in cord blood of preterm versus full-term newborns have been investigated [13].…”

“…Subsequent studies towards understanding the immunomodulatory mechanism of these cells showed that TGF-β [6] and direct cell–cell interactions might partially be involved for their immunosuppressive effects [7]. Moreover, it has been suggested that erythroid precursors promote polarization of naive CD4 + T cells to different T cell subtypes [3,8] and may alter the T-helper 1/2 (Th1/Th2) cytokine balance toward a Th2 phenotype in newborns [9]. In agreement, we have recently discovered that CD71 + erythroid cells are enriched in newborns and, because of their immunosuppressive properties, impair both the innate and adaptive immune responses in newborns [10–12].…”

Stress Erythropoiesis is a Key Inflammatory Response

“…Inflammatory signaling through TLRs plays a key role in this response as mice with mutations in the downstream signaling molecules, Myd88 and TRIF, fail to induce splenic erythropoiesis after infection. Salmonella infection also increases Epo production by the kidney and liver, which contributes to the increase in splenic stress erythropoiesis [99][100][101]. Like the infection models, sterile inflammation models show increased splenic erythropoiesis.…”

Erythroid Lineage Cells in the Liver: Novel Immune Regulators and Beyond

“…Immune potency of these CD71+ erythroid cells was also observed in neonatal salmonella infection but it seemed to have both positive and negative consequences for host immunity. 44 Immunosuppression mediated by CD71+ erythroid cells is also crucial for homeostasis in the perinatal period, as it has been shown to bring down TNF-alpha and IFN-gamma production through arginase-2 activity and PD-1/programmed death ligand-1 (PDL-1), contributing to fetomaternal tolerance. 22 The critical window of erythropoiesis in the neonatal period suggests erythroid lineage cells may play an important role in neonatal immunity.…”