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Neutrophil-derived cathelicidin promotes adhesion of classical monocytes.

ABSTRACT: RATIONALE:The leukocyte response in acute inflammation is characterized by an initial recruitment of neutrophils preceding a second wave of monocytes. Neutrophil-derived granule proteins were suggested to hold an important role in this cellular switch. The exact mechanisms by which neutrophils mediate these processes are only partially understood. OBJECTIVE:To investigate the role of neutrophils and their granule contents in the adhesion of monocyte subpopulations in acute inflammation. METHODS AND RESULTS:Here, we show that neutrophil-derived cathelicidins (human: LL37, mouse: CRAMP) induce adhesion of classical monocytes but not of nonclassical monocytes in the mouse cremaster muscle and in in vitro flow chamber assays. CRAMP is released from emigrated neutrophils and then transported across the endothelium, where it is presented to rolling leukocytes. Endothelial-bound cathelicidin activates formyl-peptide receptor 2 on classical monocytes, resulting in monocytic ?1- and ?2-integrin conformational change toward an extended, active conformation that allows for adhesion to their respective ligands, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. CONCLUSIONS:These data elucidate a novel mechanism of neutrophil-mediated monocyte recruitment, which could be targeted in conditions where recruitment of classical monocytes plays an unfavorable role.

SUBMITTER: Wantha S

PROVIDER: S-EPMC3702173 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Neutrophil-derived cathelicidin promotes adhesion of classical monocytes.

Wantha Sarawuth S Alard Jean-Eric JE Megens Remco T A RT van der Does Anne M AM Döring Yvonne Y Drechsler Maik M Pham Christine T N CT Wang Ming-Wei MW Wang Ji-Min JM Gallo Richard L RL von Hundelshausen Philipp P Lindbom Lennart L Hackeng Tilman T Weber Christian C Soehnlein Oliver O

Circulation research 20130102 5

<h4>Rationale</h4>The leukocyte response in acute inflammation is characterized by an initial recruitment of neutrophils preceding a second wave of monocytes. Neutrophil-derived granule proteins were suggested to hold an important role in this cellular switch. The exact mechanisms by which neutrophils mediate these processes are only partially understood.<h4>Objective</h4>To investigate the role of neutrophils and their granule contents in the adhesion of monocyte subpopulations in acute inflamm ...[more]

PMID: 23283724

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Project description:BackgroundBone generation and maintenance involve osteoblasts, osteoclasts, and osteocytes which originate from unique precursors and rely on key growth factors for differentiation. However, an incomplete understanding of bone forming cells during wound healing has led to an unfilled clinical need such as nonunion of bone fractures. Since circulating monocytes are often recruited to sites of injury and may differentiate into various cell types including osteoclasts, we investigated the possibility that circulating monocytes in the context of tissue injury may also contribute to bone repair. In particular, we hypothesized that LL-37 (produced from hCAP-18, cathelicidin), which recruits circulating monocytes during injury, may play a role in bone repair.Methods and findingsTreatment of monocytes from blood with LL-37 for 6 days resulted in their differentiation to large adherent cells. Growth of LL-37-differentiated monocytes on osteologic discs reveals bone-like nodule formation by scanning electron microscopy (SEM). In vivo transplantation studies in NOD/SCID mice show that LL-37-differentiated monocytes form bone-like structures similar to endochondral bone formation. Importantly, LL-37-differentiated monocytes are distinct from conventional monocyte-derived osteoclasts, macrophages, and dendritic cells and do not express markers of the mesenchymal stem cells (MSC) lineage, distinguishing them from the conventional precursors of osteoblasts. Furthermore, LL-37 differentiated monocytes express intracellular proteins of both the osteoblast and osteoclast lineage including osteocalcin (OC), osteonectin (ON), bone sialoprotein II (BSP II), osteopontin (OP), RANK, RANKL, MMP-9, tartrate resistant acid phosphatase (TRAP), and cathepsin K (CK).ConclusionBlood derived monocytes treated with LL-37 can be differentiated into a novel bone forming cell that functions both in vitro and in vivo. We propose the name monoosteophil to indicate their monocyte derived lineage and their bone forming phenotype. These cells may have wide ranging implications in the clinic including repair of broken bones and treatment of osteoporosis.

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Neutrophil-derived cathelicidin promotes adhesion of classical monocytes.

Publications

Neutrophil-derived cathelicidin promotes adhesion of classical monocytes.

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