Identification of the Cellular Sensor That Stimulates the Inflammatory Response to Sterile Cell Death

Abstract

Cell death provokes a robust inflammatory response. We have previously shown that this response is dependent on IL-α. Here we investigate the cellular mechanism used by a host to sense cell death, produce IL-α and also the role of IL-β in this response. In almost all cases examined, the IL-1 that stimulated the death-induced inflammatory response came from the host rather than the cell that was dying. In these situations, host bone marrow-derived cells were the key source of the IL-α that was required for the inflammatory response. Conditional cellular depletion and reconstitution in CD11b promoter- driven diphtheria toxin receptor transgenic mice revealed that host macrophages played an essential role in the generation of the inflammatory response and were the source of the required IL-α. In addition, we found a role for IL-β in the death-induced inflammatory response and that this cytokine was generated by both bone marrow-derived and radioresistant host cells. The one exception to these findings was that when dendritic cells were injected into mice, they provided a portion of the IL-1 that stimulated inflammation, and this was observed whether the dendritic cells were live or necrotic. Together, these findings demonstrate that macrophages play a key role as the primary sentinels that are required to sense and report cell death in ways that initiate the inflammatory response. One key way they accomplish this important task is by producing IL-α that is needed to initiate the inflammatory response.

NADPH oxidase controls neutrophilic response to sterile inflammation in mice by regulating the IL-1α/G-CSF axis

“…24 As already mentioned, resident macrophages from naive WT and X-CGD mice expressed comparable levels of IL-1a and IL-1b transcripts (supplemental Figure 2) although lack IL-1a and IL-1b protein in cell lysates (data not shown). To determine whether periodate injury induced ROS, we harvested peritoneal cells 30 minutes after periodate, finding increased ROS production by WT but not X-CGD cells (supplemental Figure 5).…”

“…19,21 In particular, the early release of IL-1a from sentinel peritoneal macrophages in response to injected necrotic cells or uric acid crystals drives neutrophil recruitment by inducing the production of inflammatory mediators from surrounding nonhematopoietic cells. 19,[22][23][24] In the current study, we show that DAMP-induced peritoneal injury in X-CGD mice resulted in excessive local production of IL-1a, leading to increased G-CSF levels. Consequently, X-CGD mice had increased peripheral neutrophilia and excessive neutrophilic exudation into the peritoneum leading to prolonged inflammation.…”

“…Prior studies showed that IL-1a production by sentinel macrophages drives the neutrophilic response to inflammation induced by necrotic cells. 22,24 In CGD, elevated production of IL-1a following periodate-induced tissue injury increased G-CSF-induced neutrophilia that exacerbated inflammation. We also showed that X-CGD resident macrophages released excessive IL-1a in response to DAMPs in vitro, and marrow transplantation studies showed that NADPH oxidasedeficient hematopoietic cells were necessary and sufficient for the exaggerated response in vivo.…”

Microbiota signalling through MyD88 is necessary for a systemic neutrophilic inflammatory response

“…25 Therefore, we quantified the numbers of resident macrophages (CD11b Neutrophil extravasation through blood vessels into tissues is facilitated by cell adhesion molecules expressed by neutrophils and the endothelium. Neutrophils in the blood of flora-deficient animals showed similar or (higher) percentages and mean fluorescence intensity of expression of cell adhesion molecules like CD44, CD62 ligand, and the chemokine receptor, chemokine (C-X-C motif) receptor 2 (CXCR2) (Fig.…”

Relationship of serum uric acid level with non‐alcoholic fatty liver disease and its inflammation progression in non‐obese adults

“…25,26 When macrophages sense the presence of DAMPs they are stimulated to produce proinflammatory cytokines that then induce inflammation. 27 It has been confirmed that uric acid is one of the important DAMPs. 28,29 Does uric acid act as a DAMP by stimulating macrophages to produce pro-inflammatory cytokines and then induce inflammation progression in non-obese adults?…”