Neutrophil Chemokines KC and Macrophage-Inflammatory Protein-2 Are Newly Synthesized by Tissue Macrophages Using Distinct TLR Signaling Pathways

Abstract

Neutrophils are the first immune cells to migrate into infected tissue sites. Therefore an important step in the initiation of an immune response is the synthesis of the neutrophil-recruiting chemokines. In this in vivo study in mice, we show that resident tissue macrophages are the source of the major neutrophil chemoattractants, KC and MIP-2. Synthesis of these chemokines is rapidly regulated at the transcriptional level by signaling through TLR2, TLR3, and TLR4 that have diverse specificities for pathogens. The major and alternative TLR signaling pathways are characterized by the adaptor proteins MyD88 or TRIF, respectively. KC and MIP-2 are both produced by signaling through MyD88. However MIP-2, but not KC, is also synthesized through the TRIF adaptor protein, identifying it as a new product of this alternative pathway. Use of both pathways by TLR4 ensures maximal levels of KC and MIP-2 that lead to robust neutrophil recruitment. However the MIP-2 generated exclusively by the TRIF pathway is still sufficient to cause an influx of neutrophils. In summary we show that TLR signaling by tissue macrophages directly controls the synthesis of neutrophil-attracting chemokines that are essential for the earliest recruitment step in the innate immune response to microbial challenge.

G-CSF–mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands

“…However, the macrophages were able to produce these chemokines after lipopolysaccharide stimulation, as shown previously. 20 In agreement with these observations, the human megakaryocyte cell line MEG-01 released abundant amounts of IL-8, a human KC/MIP-2 homolog, in vitro ( Figure 4F). Furthermore, Eash et al described endothelial cells and osteoblasts as sources of Cxcr2 ligands.…”

“…The induction of the chemokines KC (Cxcl1) and MIP-2 (Cxcl2) is a hallmark of inflammation and infection in peripheral tissues. 3,20 Recruitment of neutrophils to inflamed sites is mediated by these chemokines via their receptor Cxcr2, 3,20,21 and direct injection of KC/MIP-2 is capable of mobilizing neutrophils in vivo. 3 In addition, a recent study in BM chimeras has shown that the expression of Cxcr2 on neutrophils is important for their mobilization.…”

Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

“…Thus, in the i.p. infection models used in this study, resident peritoneal macrophages were likely one of the cell types responsible for the IDR-1002-induced chemokine production, as peritoneal macrophages are known to be an important source of chemokines for leukocyte recruitment during peritoneal infections (53)(54)(55). However, a contribution of other cell types to the IDR-1002-stimulated chemokine production cannot be ruled out, and these cell types may include mast cells and peritoneal mesothelial cells, which are also known to be important chemokine producers in some models of peritonitis (55)(56)(57)(58).…”

Early expression of local cytokines during systemic Candida albicans infection in a murine intravenous challenge model

“…CXCL-1 is involved in the mobilization of leukocyte infiltrates, particularly neutrophil, towards the site of infection and is transcriptionally regulated by signalling through toll-like receptor (TLR) 2, 3 and 4 (27). In the present study, CXCL-1 was statistically increased in the kidney only at 72 h post-infection.…”