Junctional adhesion molecule-A deletion increases phagocytosis and improves survival in a murine model of sepsis

Klingensmith, Nathan J.; Fay, Katherine; Swift, David A; Bazzano, Julia Mr; Lyons, John D.; Chen, Ching-Wen; Meng, Mei; Ramonell, Kimberly M.; Liang, Zhe; Burd, Eileen M.; Parkos, Charles A.; Ford, Mandy L.; Coopersmith, Craig M.

doi:10.1172/jci.insight.156255

Cited by 10 publications

(7 citation statements)

References 85 publications

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“…Alternatively, some changes in macrophage phenotype previously observed in JAM-A-deficient mice may be secondary effects of whole-body JAM-A deletion. Such secondary effects on myeloid cell activity were demonstrated by a recent study: septic whole-body JAM-A knock-out mice generate an augmented B cell response and higher systemic levels of opsonizing IgA antibodies, which, in turn, leads to enhanced phagocytosis of bacteria by circulating neutrophils ( 16 ).…”

Section: Discussionmentioning

confidence: 95%

“…Notably, whole-body JAM-A-deficient mice show increased vascular permeability and compromised intestinal epithelial barrier due to impaired tight junction function, which alters systemic immune homeostasis ( 13 – 16 ). Hence, generation of lineage-specific knock-out mouse models is essential to avoid these systemic effects and unequivocally define the role of JAM-A in the regulation of myeloid cell recruitment and phenotype in cancer.…”

Section: Introductionmentioning

confidence: 99%

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Junctional adhesion molecule-A is dispensable for myeloid cell recruitment and diversification in the tumor microenvironment

et al. 2022

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Junctional adhesion molecule-A (JAM-A), expressed on the surface of myeloid cells, is required for extravasation at sites of inflammation and may also modulate myeloid cell activation. Infiltration of myeloid cells is a common feature of tumors that drives disease progression, but the function of JAM-A in this phenomenon and its impact on tumor-infiltrating myeloid cells is little understood. Here we show that systemic cancer-associated inflammation in mice enhanced JAM-A expression selectively on circulating monocytes in an IL1β-dependent manner. Using myeloid-specific JAM-A-deficient mice, we found that JAM-A was dispensable for recruitment of monocytes and other myeloid cells to tumors, in contrast to its reported role in inflammation. Single-cell RNA sequencing revealed that loss of JAM-A did not influence the transcriptional reprogramming of myeloid cells in the tumor microenvironment. Overall, our results support the notion that cancer-associated inflammation can modulate the phenotype of circulating immune cells, and we demonstrate that tumors can bypass the requirement of JAM-A for myeloid cell recruitment and reprogramming.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Junctional adhesion molecule-A is dispensable for myeloid cell recruitment and diversification in the tumor microenvironment

et al. 2022

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“…Plk3 -/mouse survival is independent of potential alterations to gut microbiota It was reported that modifications of the mouse genome can influence gut microbiota 23 . To determine if alterations in gut microbiota contribute to reduced mortality observed in Plk3 -/mice following CLP, we performed CS injections whereby cecal contents from WT mice were IP injected into Plk3 -/mice and vice versa.…”

Section: Plk3 Deletion Confers Protection From Sepsismentioning

confidence: 99%

Plk3 Regulates Bacteremia and Supports Sepsis

Kostyak,

Sarojini,

Naik

et al. 2024

Preprint

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ObjectiveSepsis, which is the body’s response to overwhelming infection, can lead to septic shock, characterized by thrombocytopenia, hypotension, and organ damage. Polo-like kinase 3 (Plk3) is a ubiquitously expressed serine/threonine kinase, but its exact role in immune function is unknown.Approach and ResultsWe usedPlk3−/−and WT mice to evaluate the function of Plk3 in several models of severe sepsis. We found that WT mice die within 48 hours of 100% cecal ligation and puncture (CLP), whilePlk3−/−mice survive. Survival following cecal slurry (CS) injection mirrored that of CLP as recipient WT mice succumbed, while recipientPlk3−/−mice survived. Analysis of bacterial load 24 hours after CLP revealed that WT blood and peritonea were loaded with bacteria, but bacteria were virtually undetectable in the peritonea or blood ofPlk3−/−mice. To determine if bacteria infiltrate the blood ofPlk3−/−mice shortly after infection, we measured bacteria 1 and 3 hours after CS injection. We found a time-dependent increase in bacteria in the blood of WT mice that was not observed inPlk3−/−mice. To determine if the lack of bacteria in the blood ofPlk3−/−mice is due to enhanced clearance, we injectedE. coliIV into WT andPlk3−/−mice. We found 75% mortality for both WT andPlk3−/−mice within 72 hours following IV injection suggesting that survival ofPlk3−/−mice following enteric infection is likely due to reduced bacteremia.ConclusionCollectively our data suggest that Plk3 supports the systemic dissemination of bacteria and subsequent sepsis following enteric infection.

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“…JAM-A is localized in tight junctions of endothelial and epithelial cells. In addition, JAM-A is expressed by circulating cells, including monocytes, lymphocytes, neutrophils, platelets, and erythrocytes [16,19,22,23]. Interestingly, JAM-A has been described to control leukocyte adhesion and diapedesis across the vascular endothelium in vitro and in vivo [24,25].…”

Section: Introductionmentioning

confidence: 99%

Junctional adhesion molecule‐A deficient mice are protected from severe experimental autoimmune encephalomyelitis

Berve,

Michel,

Tietz

et al. 2024

Eur J Immunol

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In multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), early pathological features include immune cell infiltration into the central nervous system (CNS) and blood–brain barrier (BBB) disruption. We investigated the role of junctional adhesion molecule‐A (JAM‐A), a tight junction protein, in active EAE (aEAE) pathogenesis. Our study confirms JAM‐A expression at the blood–brain barrier and its luminal redistribution during aEAE. JAM‐A deficient (JAM‐A−/−) C57BL/6J mice exhibited milder aEAE, unrelated to myelin oligodendrocyte glycoprotein‐specific CD4+ T‐cell priming. While JAM‐A absence influenced macrophage behavior on primary mouse brain microvascular endothelial cells (pMBMECs) under flow in vitro, it did not impact T‐cell extravasation across primary mouse brain microvascular endothelial cells. At aEAE onset, we observed reduced lymphocyte and CCR2+ macrophage infiltration into the spinal cord of JAM‐A−/− mice compared to control littermates. This correlated with increased CD3+ T‐cell accumulation in spinal cord perivascular spaces and brain leptomeninges, suggesting JAM‐A absence leads to T‐cell trapping in central nervous system border compartments. In summary, JAM‐A plays a role in immune cell infiltration and clinical disease progression in aEAE.

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Junctional adhesion molecule-A deletion increases phagocytosis and improves survival in a murine model of sepsis

Cited by 10 publications

References 85 publications

Junctional adhesion molecule-A is dispensable for myeloid cell recruitment and diversification in the tumor microenvironment

Junctional adhesion molecule-A is dispensable for myeloid cell recruitment and diversification in the tumor microenvironment

Plk3 Regulates Bacteremia and Supports Sepsis

Junctional adhesion molecule‐A deficient mice are protected from severe experimental autoimmune encephalomyelitis

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