CD13 is essential for inflammatory trafficking and infarct healing following permanent coronary artery occlusion in mice

Pereira, Flavia E.; Cronin, Chunxia; Ghosh, Monisha; Zhou, Si Yuan; Agosto, Mariela Melissa Rivera; Subramani, Jaganathan; Wang, Ruibo; Shen, Jianbing; Schacke, Wolfgang; Liang, Brannen; Yang, Tie Hong; McAulliffe, Beata; Liang, Bruce T.; Shapiro, Linda H.

doi:10.1093/cvr/cvt155

Cited by 30 publications

(44 citation statements)

References 50 publications

(64 reference statements)

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“…In keeping with the defective CD13 KO MSC morphogenesis and capillary network formation, we also find that capillary density is decreased and the capillaries that are formed are immature and poorly branched in the injuries of recipients of the CD13 KO MSCs, clearly contributing to reduced functional recovery. In support of this notion, we have found that angiogenesis is universally impaired in CD13 KO animals subjected to ischemic injury models (Pereira et al, 2013;Rahman et al, 2013) or tumors (Pasqualini et al, 2000;Bhagwat et al, 2003). Alternatively, the implanted MSCs have been described as a minor source of healthy precursor cells and wild type tissue-resident endothelial precursors are critical for neovessel formation in the wound.…”

Section: Discussionmentioning

confidence: 85%

CD13 promotes mesenchymal stem cell-mediated regeneration of ischemic muscle

et al. 2014

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Mesenchymal stem cells (MSCs) are multipotent, tissue-resident cells that can facilitate tissue regeneration and thus, show great promise as potential therapeutic agents. Functional MSCs have been isolated and characterized from a wide array of adult tissues and are universally identified by the shared expression of a core panel of MSCs markers. One of these markers is the multifunctional cell surface peptidase CD13 that has been shown to be expressed on human and murine MSCs from many tissues. To investigate whether this universal expression indicates a functional role for CD13 in MSC biology we isolated, expanded and characterized MSCs from bone marrow of wild type (WT) and CD13KO mice. Characterization of these cells demonstrated that both WT and CD13KO MSCs expressed the full complement of MSC markers (CD29, CD44, CD49e, CD105, Sca1), showed comparable proliferation rates and were capable of differentiating toward the adipogenic and osteogenic lineages. However, MSCs lacking CD13 were unable to differentiate into vascular cells, consistent with our previous characterization of CD13 as an angiogenic regulator. Compared to WT MSCs, adhesion and migration on various extracellular matrices of CD13KO MSCs were significantly impaired, which correlated with decreased phospho-FAK levels and cytoskeletal alterations. Crosslinking human MSCs with activating CD13 antibodies increased cell adhesion to endothelial monolayers and induced FAK activation in a time dependent manner. In agreement with these in vitro data, intramuscular injection of CD13KO MSCs in a model of severe ischemic limb injury resulted in significantly poorer perfusion, decreased ambulation, increased necrosis and impaired vascularization compared to those receiving WT MSCs. This study suggests that CD13 regulates FAK activation to promote MSC adhesion and migration, thus, contributing to MSC-mediated tissue repair. CD13 may present a viable target to enhance the efficacy of mesenchymal stem cell therapies.

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Section: Discussionmentioning

confidence: 85%

CD13 promotes mesenchymal stem cell-mediated regeneration of ischemic muscle

et al. 2014

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“…As an extracellular peptidase, CD13 cleaves single amino acid residues from small peptides, and therefore, its substrates vary depending on the tissue where it is expressed. However, our observations have clearly shown that CD13 is a surprisingly multifunctional molecule that often acts independently of its enzymatic activity to regulate diverse processes such as angiogenesis, inflammatory trafficking, Ag presentation, cell-cell adhesion, coronavirus infection, and maintenance of the stem cell niche (9)(10)(11)(12)(13)(14). Although it is difficult to reconcile how a single molecule can regulate such apparently disparate functions, the fact that CD13 participates in the endocytosis of various receptors may underlie its wide range of activities.…”

Section: Discussionmentioning

confidence: 90%

“…We have identified CD13 as an inflammatory adhesion molecule that is required for optimal monocyte trafficking to sites of ischemic injury in numerous tissues (10,(12)(13)(14)21). In particular, in a model of ischemic peripheral muscle injury, the ratios of infiltrating monocytes in ischemic tissues from animals lacking CD13 were markedly altered, resulting in a distinctly "prohealing" cytokine milieu (13,14,22).…”

Section: Cd13 Regulates the Tlr4 Response To Damps Released In Ischemmentioning

confidence: 99%

“…The CD13/aminopeptidase N membrane metallopeptidase is highly expressed on myeloid cells and activated endothelial cells and participates in various innate and adaptive immune mechanisms (9)(10)(11)(12)(13)(14). Recently, we found that CD13 negatively regulates receptor-mediated, dynamin-dependent Ag uptake by dendritic cells (DCs) to control the adaptive immune response (9).…”

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confidence: 99%

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CD13 Restricts TLR4 Endocytic Signal Transduction in Inflammation

Ghosh

Subramani

Rahman

et al. 2015

The Journal of Immunology

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Dysregulation of the innate immune response underlies numerous pathological conditions. The Toll-like Receptor 4 (TLR4) is the prototypical sensor of infection or injury that orchestrates the innate response via sequential activation of both cell-surface and endocytic signaling pathways that trigger distinct downstream consequences. CD14 binds and delivers LPS to TLR4 and has been identified as a positive regulator of TLR4 signal transduction. It is logical that negative regulators of this process also exist to maintain the critical balance required for fighting infection, healing damaged tissue and resolving inflammation. We showed that CD13 negatively modulates receptor-mediated Ag uptake in dendritic cells to control T-cell activation in adaptive immunity. Here we report that myeloid CD13 governs internalization of TLR4 and subsequent innate signaling cascades, activating IRF-3 independently of CD14. CD13 is co-internalized with TLR4, CD14 and dynamin into Rab5+ early endosomes upon LPS treatment. Importantly, in response to TLR4 ligands HMGB1 and LPS, pIRF-3 activation and transcription of its target genes is enhanced in CD13KO DCs while TLR4 surface signaling remains unaffected, resulting in a skewed inflammatory response. This finding is physiologically relevant as ischemic injury in vivo provoked identical TLR4 responses. Finally, CD13KO mice showed significantly enhanced IFNβ-mediated signal transduction via JAK-STAT, escalating iNOS transcription levels and promoting accumulation of oxidative stress mediators and tissue injury. Mechanistically, inflammatory activation of macrophages upregulates CD13 expression and CD13 and TLR4 co-immunoprecipitate. Therefore, CD13 negatively regulates TLR4 signaling, thereby balancing the innate response by maintaining the inflammatory equilibrium critical to innate immune regulation.

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“…8 In the current study, using adoptive transfer, antibody blocking and gain of function models we demonstrate that both endothelial and monocytic CD13 expression is essential for inflammatory cell infiltration in response to thioglycollate (TG) -induced peritonitis, confirming that altered trafficking contributes to the phenotypes found in our in vivo studies. 7,8 In addition, species-and domain-specific chimeras verified that the CD13 C-terminus determines monocyte/endothelial adhesion and myeloid cell trafficking. Therefore, this investigation confirms the requirement for CD13 expression for adhesion and trafficking of myeloid cell subsets and further clarifies the molecular mechanisms underlying CD13-mediated monocyte/endothelial adhesion during the process of cellular migration in vivo.…”

Section: M M U N O L O G Y O R I G I N a L A R T I C L Ementioning

confidence: 84%

Molecular mechanisms regulating CD13‐mediated adhesion

et al. 2014

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SummaryCD13/Aminopeptidase N is a transmembrane metalloproteinase that is expressed in many tissues where it regulates various cellular functions. In inflammation, CD13 is expressed on myeloid cells, is up-regulated on endothelial cells at sites of inflammation and mediates monocyte/endothelial adhesion by homotypic interactions. In animal models the lack of CD13 alters the profiles of infiltrating inflammatory cells at sites of ischaemic injury. Here, we found that CD13 expression is enriched specifically on the pro-inflammatory subset of monocytes, suggesting that CD13 may regulate trafficking and function of specific subsets of immune cells. To further dissect the mechanisms regulating CD13-dependent trafficking we used the murine model of thioglycollate-induced sterile peritonitis.

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CD13 is essential for inflammatory trafficking and infarct healing following permanent coronary artery occlusion in mice

Abstract: In the ischaemic heart, while compensatory mechanisms apparently relieve potential angiogenic defects, CD13 is essential for proper trafficking of the inflammatory cells necessary to prime and sustain the reparative response, thus promoting optimal post-infarction healing.

Cited by 30 publications

References 50 publications

CD13 promotes mesenchymal stem cell-mediated regeneration of ischemic muscle

CD13 promotes mesenchymal stem cell-mediated regeneration of ischemic muscle

CD13 Restricts TLR4 Endocytic Signal Transduction in Inflammation

Molecular mechanisms regulating CD13‐mediated adhesion

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