Annexin‐1‐deficient mice exhibit spontaneous airway hyperresponsiveness and exacerbated allergen‐specific antibody responses in a mouse model of asthma

Ng, F. S. P.; Wong, Yin Kwan; Guan, Sheng-Uei; Mustafa, Fatima; Kajiji, Tasneem; Bist, Pradeep; Biswas, Subhra K.; Wong, W.S. Fred; Lim, Lina H.K.

doi:10.1111/j.1365-2222.2011.03855.x

Cited by 46 publications

(48 citation statements)

References 38 publications

(55 reference statements)

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“…However, its role in the regulation of adaptive immune responses and T cell activation is poorly understood. We and other investigators demonstrated that AnxA1 exerts inhibitory effects in in vivo models of the adaptive immune response (13,14) and in in vitro studies of Ag-specific T cell activation (15,16). In contrast, other studies revealed that AnxA1 promotes Th1 responses while inhibiting Th2 responses (17)(18)(19).…”

Section: Discussionmentioning

confidence: 89%

“…AnxA1 is expressed in T cells in humans and mice but less abundantly so than in circulating neutrophils and monocytes (9)(10)(11)(12). Several studies provide evidence that AnxA1 acts to inhibit T cell-dependent models of inflammation (13)(14)(15)(16). In contrast, other studies suggest that AnxA1 plays a facilitatory role in T cell-mediated responses (17)(18)(19).…”

mentioning

confidence: 79%

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Deficiency of Annexin A1 in CD4+ T Cells Exacerbates T Cell–Dependent Inflammation

Yang

Song

Deane

et al. 2013

The Journal of Immunology

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Annexin A1 (AnxA1) is recognized as an endogenous anti-inflammatory molecule. However, its effects on the adaptive immune response and, in particular, on T cells remain unclear. In this study, we investigated the actions of AnxA1 in three distinct models of T cell–mediated inflammation. In contact hypersensitivity, collagen-induced arthritis, and inflammation induced by OT-II TCR transgenic T cells responding to OVA, AnxA1 deficiency significantly increased Ag-induced T cell proliferation and the resultant level of inflammation. In the contact hypersensitivity model, this was associated with increased adhesion of CD4+ T cells, CD8+ T cells, and neutrophils in the dermal microvasculature, as well as increased T cell expression of RORγt and IL-17A. In collagen-induced arthritis, deficiency of endogenous AnxA1 increased susceptibility to arthritis and Ag-specific T cell activation. Deficiency of AnxA1 also increased OVA-induced cutaneous delayed-type hypersensitivity and IFN-γ and IL-17 release. Transfer experiments using CD4+ T cells from AnxA1−/− mice demonstrated that the absence of AnxA1 solely in T cells resulted in increased inflammatory responses in wild-type recipients. Similarly, experiments using AnxA1−/− OT-II CD4+ T cells demonstrated that the absence of AnxA1 in T cells was sufficient to induce increased Ag-specific CD4+ T cell proliferation in vivo, augment T cell production of IFN-γ, IL-17, TNF, and IL-6, and increase Akt, ERK, and p38 activation. Together, these findings indicate that T cell–expressed AnxA1 functions to attenuate T cell–driven inflammatory responses via T cell–intrinsic effects on intracellular signaling, proliferation, and Th1/Th17 cytokine release.

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Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 79%

Deficiency of Annexin A1 in CD4+ T Cells Exacerbates T Cell–Dependent Inflammation

Yang

Song

Deane

et al. 2013

The Journal of Immunology

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“…The tis-negative regulation of Th2 cell responses in the lung. Indeed, mice deficient for annexin A1, a phospholipase A2 inhibitor encoded by the Anxa1 gene, or for RUNX3, the transcription factor encoded by the Runx3 gene, spontaneously develop asthma-like diseases (46,48). Moreover, mice lacking the low-density lipoprotein receptor, the product of Ldlr, are more prone than are WT controls to developing airway hyperreactivity when sensitized to allergens (50).…”

Section: Discussionmentioning

confidence: 99%

“…Microarray analyses revealed that lung rEos specifically expressed several genes, such as Anxa1 (46), Nedd4 (47), Runx3 (48), Serpinb1a (49), and Ldlr (50), that are involved in the maintenance of lung immune homeostasis. Some of these genes are implicated in the …”

Section: Discussionmentioning

confidence: 99%

“…iEos had high expression of several proinflammatory genes such as Slc3a2 (39), Tlr4 (40), C3ar1 (41,42), Il13ra1 (43), and Il6 (44), consistent with the known function of iEos as proinflammatory effector cells ( Figure 3B). In contrast, rEos expressed several genes such as Anxa1 (45,46), Nedd4 (47), Runx3 (48), Serpinb1a (49), and Ldlr (50) that are implicated in the negative regulation of immune responses and tissue homeostasis ( Figure 3B). These analyses suggested that, in addition to their unique localization and morphology, rEos and iEos were also functionally different.…”

Section: Cd101mentioning

confidence: 99%

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Lung-resident eosinophils represent a distinct regulatory eosinophil subset

Mesnil

Raulier

Paulissen

et al. 2016

Journal of Clinical Investigation

380

506

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Increases in eosinophil numbers are associated with infection and allergic diseases, including asthma, but there is also evidence that eosinophils contribute to homeostatic immune processes. In mice, the normal lung contains resident eosinophils (rEos), but their function has not been characterized. Here, we have reported that steady-state pulmonary rEos are IL-5-independent parenchymal Siglec-FintCD62L+CD101lo cells with a ring-shaped nucleus. During house dust mite-induced airway allergy, rEos features remained unchanged, and rEos were accompanied by recruited inflammatory eosinophils (iEos), which were defined as IL-5-dependent peribronchial Siglec-FhiCD62L-CD101hi cells with a segmented nucleus. Gene expression analyses revealed a more regulatory profile for rEos than for iEos, and correspondingly, mice lacking lung rEos showed an increase in Th2 cell responses to inhaled allergens. Such elevation of Th2 responses was linked to the ability of rEos, but not iEos, to inhibit the maturation, and therefore the pro-Th2 function, of allergen-loaded DCs. Finally, we determined that the parenchymal rEos found in nonasthmatic human lungs (Siglec-8+CD62L+IL-3Rlo cells) were phenotypically distinct from the iEos isolated from the sputa of eosinophilic asthmatic patients (Siglec-8+CD62LloIL-3Rhi cells), suggesting that our findings in mice are relevant to humans. In conclusion, our data define lung rEos as a distinct eosinophil subset with key homeostatic functions

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Therapeutic anti‐amyloid β antibodies cause neuronal disturbances

Adhikari

Khan

Mikhael

et al. 2022

Alzheimer's & Dementia

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Recent published clinical trial safety data showed that 41% of Alzheimer patients experienced amyloid-related imaging abnormalities (ARIA), marks of microhemorrhages and oedema in the brain, following administration of Biogen's Aduhelm/ aducanumab (amino acids 3-7 of the Aβ peptide). Similarly, Janssen/Pfizer's Bapineuzumab (amino acids 1-5 of the Aβ peptide) and Roche's Gantenerumab (amino acids 2-11/18-27 of the Aβ peptide) also displayed ARIA in clinical trials, including microhemorrhage and focal areas of inflammation or vasogenic oedema respectively. The molecular mechanisms underlying ARIA caused by therapeutic anti-Aβ antibodies remain largely unknown, however, recent reports demonstrated that therapeutic antiprion antibodies activate both neuronal apoptotic and allergenic proteomes following cross-linking cellular prion protein. Here, we report that treatment of human induced pluripotent stem cellsderived neurons (HSCN) from a non-demented donor, co-cultured with human primary microglia with anti-Aβ1-6, or anti-Aβ17-23 antibodies activate a significant number of both apoptotic and allergenic-related proteins as assessed by mass spectrometry. Interestingly, a large proportion of the identified proteins included cytokines such as IL-4, IL-12, and IL-13 suggesting a type-1 hypersensitivity response. Following flow cytometry analysis, several proinflammatory cytokines were significantly elevated following anti-Aβ1-6, or anti-Aβ17-23 antibody treatment. These results justify further and more robust investigation of the molecular mechanisms of ARIA during immunotherapy study trials of AD.

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Annexin‐1‐deficient mice exhibit spontaneous airway hyperresponsiveness and exacerbated allergen‐specific antibody responses in a mouse model of asthma

Abstract: We postulate that ANXA1 is an important regulatory factor in the development of allergic disease and dysregulation of its expression can lead to pathological changes which may affect disease progression.

Cited by 46 publications

References 38 publications

Deficiency of Annexin A1 in CD4+ T Cells Exacerbates T Cell–Dependent Inflammation

Deficiency of Annexin A1 in CD4+ T Cells Exacerbates T Cell–Dependent Inflammation

Lung-resident eosinophils represent a distinct regulatory eosinophil subset

Therapeutic anti‐amyloid β antibodies cause neuronal disturbances

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