Macrophages promote epithelial proliferation following infectious and non-infectious lung injury through a Trefoil factor 2-dependent mechanism

Hung, Li-Yin; Sen, Debasish; Oniskey, Taylor K.; Katzen, Jeremey; Cohen, Noam A.; Vaughan, Andrew E.; Nieves, Wildaliz; Urisman, Anatoly; Beers, Michael F.; Krummel, Matthew F.; Herbert, De’Broski R.

doi:10.1038/s41385-018-0096-2

Cited by 56 publications

(50 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several studies with nematode-infected mice demonstrate the relevance of the balance between M1 and M2 macrophages and the molecules these cells release [18]. Notably, studies involving Heligmosomoides polygyrus [19] and Nippostrongylus brasiliensis [20], as well as the filarial nematodes Brugia malayi and Litomosoides sigmodontis [21], and the trematode Schistosoma japonicum [22] highlight an initial T-helper 1 (Th1)-M1 inflammation profile associated with tissue damage, followed by a Th2-M2 polarization that promotes tissue repair. It is clear that macrophages participate in many important immune functions following infection with helminths that are characterized by M2 signature molecules (e.g.…”

Section: Introductionmentioning

confidence: 99%

A Dual Role for Macrophages in Modulating Lung Tissue Damage/Repair during L2 Toxocara canis Infection

et al. 2019

View full text Add to dashboard Cite

Macrophages that are classically activated (M1) through the IFN-γ/STAT1 signaling pathway have a major role in mediating inflammation during microbial and parasitic infections. In some cases, unregulated inflammation induces tissue damage. In helminth infections, alternatively activated macrophages (M2), whose activation occurs mainly via the IL-4/STAT6 pathway, have a major role in mediating protection against excessive inflammation, and has been associated with both tissue repair and parasite clearance. During the lung migratory stage of Toxocara canis, the roles of M1 and M2 macrophages in tissue repair remain unknown. To assess this, we orally infected wild-type (WT) and STAT1 and STAT6-deficient mice (STAT1−/− and STAT6−/−) with L2 T. canis, and evaluated the role of M1 or M2 macrophages in lung pathology. The absence of STAT1 favored an M2 activation pattern with Arg1, FIZZ1, and Ym1 expression, which resulted in parasite resistance and lung tissue repair. In contrast, the absence of STAT6 induced M1 activation and iNOS expression, which helped control parasitic infection but generated increased inflammation and lung pathology. Next, macrophages were depleted by intratracheally inoculating mice with clodronate-loaded liposomes. We found a significant reduction in alveolar macrophages that was associated with higher lung pathology in both WT and STAT1−/− mice; in contrast, STAT6−/− mice receiving clodronate-liposomes displayed less tissue damage, indicating critical roles of both macrophage phenotypes in lung pathology and tissue repair. Therefore, a proper balance between inflammatory and anti-inflammatory responses during T. canis infection is necessary to limit lung pathology and favor lung healing.

show abstract

Section: Introductionmentioning

confidence: 99%

A Dual Role for Macrophages in Modulating Lung Tissue Damage/Repair during L2 Toxocara canis Infection

et al. 2019

View full text Add to dashboard Cite

show abstract

“…They share substantial sequence similarity, which is suggestive of a conserved function, though their biological roles are not redundant 2 . The TFFs protect the mucosal epithelium by increasing the viscoelasticity of mucus 3,4 and enhancing epithelial restitution rates [5][6][7][8][9] . TFF overexpression is prevalent in adenocarcinomas [10][11][12] and a hallmark of chronic inflammatory diseases of the respiratory tract [13][14][15] .…”

mentioning

confidence: 99%

Trefoil factors share a lectin activity that defines their role in mucus

et al. 2020

View full text Add to dashboard Cite

The mucosal epithelium secretes a host of protective disulfide-rich peptides, including the trefoil factors (TFFs). The TFFs increase the viscoelasticity of the mucosa and promote cell migration, though the molecular mechanisms underlying these functions have remained poorly defined. Here, we demonstrate that all TFFs are divalent lectins that recognise the GlcNAc-α-1,4-Gal disaccharide, which terminates some mucin-like O-glycans. Degradation of this disaccharide by a glycoside hydrolase abrogates TFF binding to mucins. Structural, mutagenic and biophysical data provide insights into how the TFFs recognise this disaccharide and rationalise their ability to modulate the physical properties of mucus across different pH ranges. These data reveal that TFF activity is dependent on the glycosylation state of mucosal glycoproteins and alludes to a lectin function for trefoil domains in other human proteins.

show abstract

“…Following lung injury, 309 the tissue repair process is promoted by immune cells including innate lymphoid cells (ILC-IIs) and 310 macrophages. 36 Epithelial restoration is initiated locally by proliferating alveolar type II (AT2) cells. 37 We 311 modeled this restoration by adding a logistic proliferation of susceptible and refractory (but not infected 38 ) 312 epithetical cells with maximum rate .…”

Section: Methods 254mentioning

confidence: 99%

Mathematical modeling explains differential SARS CoV-2 kinetics in lung and nasal passages in remdesivir treated rhesus macaques

Goyal

Duke

Cardozo-Ojeda

et al. 2020

Preprint

View full text Add to dashboard Cite

These authors contributed equally to the work. One Sentence Summary:We developed a mathematical model to explain why remdesivir has a greater antiviral effect on SARS CoV-2 in lung versus nasal passages in rhesus macaques. Abstract 1 2Remdesivir was recently demonstrated to decrease recovery time in hospitalized patients with SARS-3CoV-2 infection. In rhesus macaques, early initiation of remdesivir therapy prevented pneumonia and 4 lowered viral loads in the lung, but viral loads increased in the nasal passages five days after therapy. We 5 developed mathematical models to explain these results. We identified that 1) drug potency is slightly 6 higher in nasal passages than in lungs, 2) viral load decrease in lungs relative to nasal passages during 7 therapy because of infection-dependent generation of refractory cells in the lung, 3) incomplete drug 8 potency in the lung that decreases viral loads even slightly may allow substantially less lung damage, and 9 4) increases in nasal viral load may occur due to a slight blunting of peak viral load and subsequent 10 decrease of the intensity of the innate immune response, as well as a lack of refractory cells. We also 11 hypothesize that direct inoculation of the trachea in rhesus macaques may not recapitulate natural 12 infection as lung damage occurs more abruptly in this model than in human infection. We demonstrate 13 with sensitivity analysis that a drug with higher potency could completely suppress viral replication and 14 lower viral loads abruptly in the nasal passages as well as the lung. Results 42 Discrepant SARS CoV-2 viral loads in lungs and nasal passages in response to remdesivir treatment in 43rhesus macaques. In a recent pre-print article, 12 rhesus macaques were infected with 2.6x10 6 TCID50 of 44 SARS-CoV-2 strain nCoV-WA1-2020 via intranasal, oral, ocular and intratracheal routes and then treated 45 with either placebo or IV remdesivir (10 mg/kg loading dose followed by 5 days of 5 mg/kg) starting at 46 12 hours post infection. 5 Overall treatment resulted in reduced severity of clinical illness, less pronounced 47

show abstract

Macrophages promote epithelial proliferation following infectious and non-infectious lung injury through a Trefoil factor 2-dependent mechanism

Cited by 56 publications

References 65 publications

A Dual Role for Macrophages in Modulating Lung Tissue Damage/Repair during L2 Toxocara canis Infection

A Dual Role for Macrophages in Modulating Lung Tissue Damage/Repair during L2 Toxocara canis Infection

Trefoil factors share a lectin activity that defines their role in mucus

Mathematical modeling explains differential SARS CoV-2 kinetics in lung and nasal passages in remdesivir treated rhesus macaques

Contact Info

Product

Resources

About