Neutrophils, Not Monocyte/Macrophages, are the Major Splenic Source of Postburn IL-10

Abstract

Burn induces myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature polymorphonuclear neutrophils (PMNs) and monocytes, which protect against infection. Previous work from our laboratory demonstrated that inflammatory monocytes (iMos) were the major MDSC source of TNF-α in the postburn spleen, and we hypothesized that they were also the major source of postburn IL-10. To test this hypothesis, we examined cytokine production by postburn CCR2 knockout (KO) mice, which have fewer iMos than burn wild-type (WT) splenocytes, but equal numbers of PMNs and F4/80 macrophages. Using cell sorting and/or intracellular cytokine techniques, we examined IL-10 production by postburn PMNs and iMos. Finally, we compared IL-10 production by postburn PMNs and iMos with culture-derived MDSCs. Splenocytes from postburn CCR2 KO mice produced less IL-6 and TNF-α than WT burn splenocytes in response to LPS, but KO and WT burn splenocytes produced equal amounts of IL-10 in response to peptidoglycan. Depletion of PMNs from postburn splenocytes led to reductions in IL-10 and increases in IL-6 and TNF-α in response to peptidoglycan, but not in response to LPS. Sorting or intracellular cytokine techniques gave consistent results: Burn PMNs made more IL-10 than sham PMNs and also more IL-10 than burn or sham iMos. Polymorphonuclear neutrophil and iMos subpopulations from culture-derived MDSCs produced the same cytokine profiles in response to LPS and peptidoglycan as did the PMNs and iMos from postburn spleens: PMNs made IL-10, whereas iMos made IL-6. Finally, LPS-induced mortality of burn mice was made worse by anti-Gr-1 depletion of all PMNs and 66% of iMos from burn mice. This suggests that PMNs play a primarily anti-inflammatory role in vitro and in vivo.

Association between early airway damage-associated molecular patterns and subsequent bacterial infection in patients with inhalational and burn injury

“…These anti-inflammatory macrophages (M2) and neutrophils (N2) secrete high amounts of IL-10, a potent anti-inflammatory cytokine (5,7,22,24), and have been implicated in the dysfunctional immune response to burn injury. Excessive IL-10 has been shown to be detrimental for bacterial clearance by attenuating protective proinflammatory cytokines, such as IL-12 (25,26,28), and in our prior report elevated IL-10 was associated with increased ALI risk after burn and inhalation injury (14).…”

Programming of the Development of Tumor-Promoting Neutrophils by Mesenchymal Stromal Cells

“…Previous studies showed that increased IL-6 levels have been associated with elevated cancer risk, and also been found to be a prognostic factor for several cancer types [24]. IL-10 is emerging as a key cytokine mediating the suppressive function of neutrophils, and dampening tumor-specific immune surveillance [25,26,27]. IL-4Rα-STAT6 signaling could induce the production of ARG1 by MDSCs [28].…”

Persistent inflammation and immunosuppression

“…MDSCs, unlike terminally differentiated macrophages, express low concentrations of MHC-II and CD80/CD86, making them poor antigen presenting cells 51 . However, these MDSCs, unlike terminally differentiated macrophages and monocytes after sepsis or trauma, produce large amounts of IL-10, TNFα, RANTES, MCP1, SDF-1 and MIP1α 51,89, 90, 91 . These cells also consume large quantities of arginine, producing NO, reactive oxygen species, and peroxynitrites that are both proinflammatory and immunosuppressive.…”