Integrin αDβ2 (CD11d/CD18) Modulates Leukocyte Accumulation, Pathogen Clearance, and Pyroptosis in Experimental Salmonella Typhimurium Infection

Nascimento, Danielle de Oliveira; Vieira‐de‐Abreu, Adriana; Arcanjo, Angélica; Bozza, Patrı́cia T.; Zimmerman, Guy A.; Castro‐Faria‐Neto, Hugo C.

doi:10.3389/fimmu.2018.01128

Cited by 11 publications

(11 citation statements)

References 61 publications

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“…Thus, CR4 (CD11c/CD18) may be important for the clearance of infections mediated by pathogens that are opsonized by C4 [56,109,195,196]. In a peritoneal Salmonella Typhimurium infection model, CD11d −/− mice were characterized by diminished peritoneal infiltration of leukocytes and accordingly elevated bacterial loads [224]. Ex vivo analysis confirmed attenuated phagocytic activity of CD11d −/− macrophages, accompanied by increased cell death in the course of the inflammatory response, termed pyroptosis [225].…”

Section: Bacterial Infectionsmentioning

confidence: 97%

β2 Integrins—Multi-Functional Leukocyte Receptors in Health and Disease

Bednarczyk

Stege

Grabbe

et al. 2020

IJMS

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β2 integrins are heterodimeric surface receptors composed of a variable α (CD11a-CD11d) and a constant β (CD18) subunit and are specifically expressed by leukocytes. The α subunit defines the individual functional properties of the corresponding β2 integrin, but all β2 integrins show functional overlap. They mediate adhesion to other cells and to components of the extracellular matrix (ECM), orchestrate uptake of extracellular material like complement-opsonized pathogens, control cytoskeletal organization, and modulate cell signaling. This review aims to delineate the tremendous role of β2 integrins for immune functions as exemplified by the phenotype of LAD-I (leukocyte adhesion deficiency 1) patients that suffer from strong recurrent infections. These immune defects have been largely attributed to impaired migratory and phagocytic properties of polymorphonuclear granulocytes. The molecular base for this inherited disease is a functional impairment of β2 integrins due to mutations within the CD18 gene. LAD-I patients are also predisposed for autoimmune diseases. In agreement, polymorphisms within the CD11b gene have been associated with autoimmunity. Consequently, β2 integrins have received growing interest as targets in the treatment of autoimmune diseases. Moreover, β2 integrin activity on leukocytes has been implicated in tumor development.

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Section: Bacterial Infectionsmentioning

confidence: 97%

β2 Integrins—Multi-Functional Leukocyte Receptors in Health and Disease

Bednarczyk

Stege

Grabbe

et al. 2020

IJMS

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“…7B) that can contribute to the increased mortality of α D ‐deficient mice during endotoxemia. The increased pyroptosis was previously detected in α D ‐deficient macrophages during Salmonella typhimurium infection 46 . Apparently, neutrophils and macrophages have a similar α D β 2 ‐related molecular mechanism for the prevention of pyroptosis during inflammation.…”

Section: Discussionmentioning

confidence: 62%

“…In contrast to these results, a moderate protective effect of D 2 was detected during Salmonella typhimurium infection. 46 Specifically, the authors showed slightly reduced survival of D -deficient mice after Salmonella infection, which correlated with an increased concentration of proinflammatory cytokines, enhanced macrophage pyroptosis and a reduced ability to combat Salmonella in D −/− mice. Notably, the outcome again was associated with macrophage functions.…”

Section: Discussionmentioning

confidence: 97%

“…The increased pyroptosis was previously detected in D -deficient macrophages during Salmonella typhimurium infection. 46 Apparently, neutrophils and macrophages have a similar D 2related molecular mechanism for the prevention of pyroptosis during inflammation. Notably, the up-regulation of D 2 on neutrophils in circulation during endotoxemia and after LPS treatment in vitro supports our conclusion regarding the importance of D 2 in neutrophil functions (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Frontline Science: The expression of integrin αDβ2 (CD11d/CD18) on neutrophils orchestrates the defense mechanism against endotoxemia and sepsis

Bailey

Cui

Ardell

et al. 2021

Journal of Leukocyte Biology

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Neutrophil-macrophage interplay is a fine-tuning mechanism that regulates the innate immune response during infection and inflammation. Cell surface receptors play an essential role in neutrophil and macrophage functions. The same receptor can provide different outcomes within diverse leukocyte subsets in different inflammatory conditions. Understanding the variety of responses mediated by one receptor is critical for the development of anti-inflammatory treatments. In this study, we evaluated the role of a leukocyte adhesive receptor, integrin D 2 , in the development of acute inflammation. D 2 is mostly expressed on macrophages and contributes to the development of chronic inflammation. In contrast, we found that D -knockout dramatically increases mortality in the cecal ligation and puncture sepsis model and LPS-induced endotoxemia.This pathologic outcome of D -deficient mice is associated with a reduced number of monocytederived macrophages and an increased number of neutrophils in their lungs. However, the tracking of adoptively transferred fluorescently labeled wild-type (WT) and D −/− monocytes in WT mice during endotoxemia demonstrated only a moderate difference between the recruitment of these two subsets. Moreover, the rescue experiment, using i.v. injection of WT monocytes to Ddeficient mice followed by LPS challenge, showed only slightly reduced mortality. Surprisingly, the injection of WT neutrophils to the bloodstream of D −/− mice markedly increased migration of monocyte-derived macrophage to lungs and dramatically improves survival. D -deficient neutrophils demonstrate increased necrosis/pyroptosis. D 2 -mediated macrophage accumulation in the lungs promotes efferocytosis that reduced mortality. Hence, integrin D 2 implements a complex defense mechanism during endotoxemia, which is mediated by macrophages via a neutrophildependent pathway.

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“…In contrast to this original postulate, a study has demonstrated that CD11d/CD18 was not required for clearance of parasitized red blood cells in a murine malaria model ( 38 ). In CD11d -/- mice, peritoneal macrophages have no defect in the internalization of latex beads and phagocytosis of Salmonella Typhimurium ( 103 ). Additionally, a separate study found murine CD11d -/- neutrophils and macrophages have no defect in the phagocytosis of Escherichia Coli ( 76 ).…”

Section: Cd11d In Phagocytosismentioning

confidence: 99%

β2 Integrin CD11d/CD18: From Expression to an Emerging Role in Staged Leukocyte Migration

et al. 2021

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CD11d/CD18 is the most recently discovered and least understood β2 integrin. Known CD11d adhesive mechanisms contribute to both extravasation and mesenchymal migration – two key aspects for localizing peripheral leukocytes to sites of inflammation. Differential expression of CD11d induces differences in monocyte/macrophage mesenchymal migration including impacts on macrophage sub-set migration. The participation of CD11d/CD18 in leukocyte localization during atherosclerosis and following neurotrauma has sparked interest in the development of CD11d-targeted therapeutic agents. Whereas the adhesive properties of CD11d have undergone investigation, the signalling pathways induced by ligand binding remain largely undefined. Underlining each adhesive and signalling function, CD11d is under unique transcriptional control and expressed on a sub-set of predominately tissue-differentiated innate leukocytes. The following review is the first to capture the nearly three decades of CD11d research and discusses the emerging role of CD11d in leukocyte migration and retention during the progression of a staged immune response.

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Integrin αDβ2 (CD11d/CD18) Modulates Leukocyte Accumulation, Pathogen Clearance, and Pyroptosis in Experimental Salmonella Typhimurium Infection

Cited by 11 publications

References 61 publications

β2 Integrins—Multi-Functional Leukocyte Receptors in Health and Disease

β2 Integrins—Multi-Functional Leukocyte Receptors in Health and Disease

Frontline Science: The expression of integrin αDβ2 (CD11d/CD18) on neutrophils orchestrates the defense mechanism against endotoxemia and sepsis

β2 Integrin CD11d/CD18: From Expression to an Emerging Role in Staged Leukocyte Migration

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