IL10 trains macrophage profibrotic function after lung injury

Bhattacharyya, Aritra; Boostanpour, Kaveh; Bouzidi, Mohamed S.; Magee, Liam; Chen, Tian Y.; Wolters, Rachel; Torre, Patricia De La; Pillai, Satish K.; Bhattacharya, Mallar

doi:10.1152/ajplung.00458.2021

Cited by 17 publications

(10 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pro-fibrotic exposures (pustulan and scleroglucan) also increased BAL cell counts and macrophage concentrations. Macrophages are increasingly recognized for their role in development of pulmonary fibrosis (62–64) with excessive M2 macrophages playing a pro-fibrotic role (65). Macrophage response to BDGs has been demonstrated to be independent of the classic BDG receptors Dectin-1 and TLR2 (66, 67); because Dectin-1 is not independently responsible for Th2 sensitization in a BDG (+house dust mite) mouse model (55), macrophage recruitment and signaling might explain the fibrotic phenotype observed after exposure to these BDGs.…”

Section: Discussionmentioning

confidence: 99%

(1→3)-β-D-glucan derivatives with unique structural properties differentially affect murine lung inflammation and histology

Metwali,

Stapleton,

Hadina

et al. 2023

Preprint

View full text Add to dashboard Cite

Background: B-D-glucan (BDG) compounds are proinflammatory fungal cell wall polysaccharides known to cause respiratory pathology. However, the specific immunological effect of unique BDG structures on pulmonary inflammation is understudied. We sought to characterize the effect of four unique fungal BDGs with unique branching patterns, solubility, molecular weights and higher order structure in murine airways. Methods: Scleroglucan (1->3) (1->6)-highly branched BDG, laminarin (1->3) (1->6)-branched BDG, curdlan (1->3)-linear BDG, and pustulan (1->6)-linear BDG were assessed by nuclear magnetic resonance spectroscopy (NMR). Glucan compounds were confirmed negative for endotoxin by kinetic chromogenic Limulus amebocyte lysate assay. Each BDG was tested using an inhalation model with C3HeB/FeJ mice and compared to control mice exposed to saline and unexposed sentinels (all, n=3-19). Inhalation studies were performed using all BDGs with and without heat-inactivation (1-hr. autoclave) given BDG solubility increases after heat-inactivation. Outcomes included bronchoalveolar lavage (BAL), differential cell counts (macrophages, neutrophils, lymphocytes, and eosinophils), BALF cytokine and serum IgE and IgG2a expression (by multiplex immunoassay and ELISA). Lastly, ex vivo cultured left lung cells were BDG stimulated, and cytokines (multiplex) compared to unstimulated cells. Right lung histology was performed. Results: While each BDG affected lung inflammatory outcomes, pustulan exposure led to the most pro-inflammatory profile of all BDGs tested, including increased inflammatory infiltrate into BAL, increased serum IgE and IgG2a and increased cytokine production. Secondary stimulation of sensitized lung cells by lipopolysaccharide (LPS) significantly increased cytokine expression. Lung histology revealed significant fibrosis in lungs exposed to soluble BDGs pustulan and scleroglucan. Conclusion: Inhalation of BDGs with distinct branching patterns exhibited varying inflammatory potency and immunogenicity, which lichen-derived pustulan having the greatest effect. Glucan source and solubility should be considered in exposure and toxicological studies.

show abstract

Section: Discussionmentioning

confidence: 99%

(1→3)-β-D-glucan derivatives with unique structural properties differentially affect murine lung inflammation and histology

Metwali,

Stapleton,

Hadina

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…A major emerging theme is the role of moMacs, which support a range of pathologic phenotypes in multiple disease models ( 29 , 30 ). Lung fibrosis is no exception, with monocyte-lineage cells being shown to be associated with poor outcomes in multiple clinical cohorts ( 31 ) and in mouse models including our own prior work showing a pro-fibrotic effect of moMacs ( 1 – 3 , 6 ). This pathologic effect of macrophages has been proposed to be related to macrophage-derived factors that both support fibroblast growth and lead to fibroblast activation, including TGFβ, PDGF, and other secreted factors ( 4 – 6 ).…”

Section: Discussionmentioning

confidence: 99%

“…Our recent work profiled the fibrotic phase of lung injury at the single-cell level, revealing a subset of Cx3cr1+ macrophages that localize to clusters of activated fibroblasts and exert a profibrotic effect ( 3 ). With respect to the profibrotic mechanisms of these macrophages, one emerging view is that they activate surrounding fibroblasts by secreting cytokines and growth factors, such as TNFα, TGFβ, and PDGF ( 2 – 6 ). However, the full repertory of signals deriving from macrophages is not known.…”

Section: Introductionmentioning

confidence: 99%

Macrophage Cx43 Is Necessary for Fibroblast Cytosolic Calcium and Lung Fibrosis After Injury

et al. 2022

Self Cite

View full text Add to dashboard Cite

Macrophages are paracrine signalers that regulate tissular responses to injury through interactions with parenchymal cells. Connexin hemichannels have recently been shown to mediate efflux of ATP by macrophages, with resulting cytosolic calcium responses in adjacent cells. Here we report that lung macrophages with deletion of connexin 43 (MacΔCx43) had decreased ATP efflux into the extracellular space and induced a decreased cytosolic calcium response in co-cultured fibroblasts compared to WT macrophages. Furthermore, MacΔCx43 mice had decreased lung fibrosis after bleomycin-induced injury. Interrogating single cell data for human and mouse, we found that P2rx4 was the most highly expressed ATP receptor and calcium channel in lung fibroblasts and that its expression was increased in the setting of fibrosis. Fibroblast-specific deletion of P2rx4 in mice decreased lung fibrosis and collagen expression in lung fibroblasts in the bleomycin model. Taken together, these studies reveal a Cx43-dependent profibrotic effect of lung macrophages and support development of fibroblast P2rx4 as a therapeutic target for lung fibrosis.

show abstract

“…The effect of IL10RA upregulation on macrophages in glomerulopathy has not been well illustrated. One study on lung injury revealed high expression of IL10RA in macrophages and its induction of fibroblast activation after injury ( Bhattacharyya et al, 2022 ). VSIG4, also referred to as the complement receptor of the immunoglobulin (CRIg) superfamily, encodes a protein of v-set and immunoglobulin domain-containing 4 that is exclusively expressed on tissue-resident macrophages ( He et al, 2008 ) and is regarded as a new regulator of immunity.…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of Prognostic Biomarkers Specifically Expressed in Macrophage in IgA Nephropathy Patients Based on Integrated Bioinformatics Analyses

Ding

et al. 2022

Front. Mol. Biosci.

View full text Add to dashboard Cite

Background: Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide and a frequent cause of end-stage renal disease. The inflammation cascade due to the infiltration and activation of immune cells in glomeruli plays an essential role in the progression of IgAN. In this study, we aimed to identify hub genes involved in immune infiltration and explore potential prognostic biomarkers and therapeutic targets in IgAN.Methods: We combined the single-cell and bulk transcriptome profiles of IgAN patients and controls with clinical data. Through single-cell analysis and weighted gene co-expression network analysis (WGCNA), Gene Ontology (GO) enrichment analysis, and differentially expressed gene (DEG) analysis in the bulk profile, we identified cell-type-specific potential hub genes in IgAN. Real hub genes were extracted via validation analysis and clinical significance analysis of the correlation between the expression levels of genes and the estimated glomerular filtration rate (eGFR) in the external dataset. Gene set enrichment analysis was performed to predict the probable roles of the real hub genes in IgAN.Results: A total of eleven cell clusters were classified via single-cell analysis, among which macrophages showed a variable proportion between the IgAN and normal control samples. We recognized six functional co-expression gene modules through WGCNA, among which the black module was deemed an IgAN-related and immune-involving module via GO enrichment analysis. DEG analysis identified 45 potential hub genes from genes enriched in GO terms. A total of twenty-three potential hub genes were specifically expressed in macrophages. Furthermore, we validated the differential expression of the 23 potential hub genes in the external dataset and identified nine genes with prognostic significance as real hub genes, viz., CSF1R, CYBB, FPR3, GPR65, HCLS1, IL10RA, PLA2G7, TYROBP, and VSIG4. The real hub gens are thought to contribute to immune cell regulation, immunoreaction, and regulation of oxidative stress, cell proliferation, and material metabolism.Conclusion: In this study, we demonstrated that macrophages infiltrated the glomeruli and contributed to the inflammatory response in IgAN. Based on integrated bioinformatics analyses of single-cell and bulk transcriptome data, we highlighted nine genes as novel prognostic biomarkers, which may enable the development of innovative prognostic and therapeutic strategies for IgAN.

show abstract

IL10 trains macrophage profibrotic function after lung injury

Cited by 17 publications

References 29 publications

(1→3)-β-D-glucan derivatives with unique structural properties differentially affect murine lung inflammation and histology

(1→3)-β-D-glucan derivatives with unique structural properties differentially affect murine lung inflammation and histology

Macrophage Cx43 Is Necessary for Fibroblast Cytosolic Calcium and Lung Fibrosis After Injury

Identification and Validation of Prognostic Biomarkers Specifically Expressed in Macrophage in IgA Nephropathy Patients Based on Integrated Bioinformatics Analyses

Contact Info

Product

Resources

About