Human airway mast cells proliferate and acquire distinct inflammation-driven phenotypes during type 2 inflammation

Abstract

Mast cells (MCs) play a pathobiologic role in type 2 (T2) allergic inflammatory diseases of the airway, including asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP). Distinct MC subsets infiltrate the airway mucosa in T2 disease, including subepithelial MCs expressing the proteases tryptase and chymase (MCTC) and epithelial MCs expressing tryptase without chymase (MCT). However, mechanisms underlying MC expansion and the transcriptional programs underlying their heterogeneity are poorly understood. Here, we use flow cytometry and single-cell RNA-sequencing (scRNA-seq) to conduct a comprehensive analysis of human MC hyperplasia in CRSwNP, a T2 cytokine–mediated inflammatory disease. We link discrete cell surface phenotypes to the distinct transcriptomes of CRSwNP MCT and MCTC, which represent polarized ends of a transcriptional gradient of nasal polyp MCs. We find a subepithelial population of CD38highCD117high MCs that is markedly expanded during T2 inflammation. These CD38highCD117high MCs exhibit an intermediate phenotype relative to the expanded MCT and MCTC subsets. CD38highCD117high MCs are distinct from circulating MC progenitors and are enriched for proliferation, which is markedly increased in CRSwNP patients with aspirin-exacerbated respiratory disease, a severe disease subset characterized by increased MC burden and elevated MC activation. We observe that MCs expressing a polyp MCT–like effector program are also found within the lung during fibrotic diseases and asthma, and further identify marked differences between MCTC in nasal polyps and skin. These results indicate that MCs display distinct inflammation-associated effector programs and suggest that in situ MC proliferation is a major component of MC hyperplasia in human T2 inflammation.

Innate immune cell dysregulation drives inflammation and disease in aspirin-exacerbated respiratory disease

“…Although a population of MCs unique to AERD was not found, local NP epithelial and subepithelial MC hyperplasia was more prominent in AERD NP when compared with non-AERD NP. 44 This increased MC burden occurs concomitantly with local accumulation of MC mediators, most notably CysLTs and prostaglandins, lipid mediators that, as previously noted, are critical to the pathogenesis of AERD. The constitutive overproduction of CysLTs in the resting state and the surge in CysLT production in response to nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) is pathognomonic for AERD.…”

Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19

“…Relative to true tissue-resident abundances, we under-recovered granulocytes, likely due to the intrinsic fragility of these cell types and the cryopreservation required in our sample pipeline (Figures S2A-S2G). We recovered a small population of mast cells (GATA2, TPSB2, PTGS2) (Dwyer et al, 2021). Each cell type is represented by cells from numerous participants.…”

“…The novel coronavirus SARS-CoV-2 emerged in late 2019 and has led to one of the most devastating global pandemics in modern history. Similar to other successful respiratory viruses, high replication within the nasopharynx (Pan et al, 2020;Sanche et al, 2020) and viral shedding by asymptomatic or presymp-tomatic individuals contributes to enhanced transmissibility (Fears et al, 2020;Meyerowitz et al, 2021) and rapid community spread (Arons et al, 2020;Sakurai et al, 2020;Wang et al, 2020c). COVID-19, the disease caused by SARS-CoV-2 infection, occurs in a fraction of those infected and can carry profound morbidity and mortality.…”

Concerted changes in the pediatric single-cell intestinal ecosystem before and after anti-TNF blockade

“…The mast cells recovered in pediCD did further sub-cluster in an automated fashion, were largely marked by TPSB2 (>90%), with minimal CMA1 (<16%) expressing cells, suggesting they are largely classical MC-T cells in pediCD intestine (Figure 4d) (Dwyer et al, 2021). Intriguingly, some subsets (CD.Mstcl.AREG.ADCYAP1) were enriched for IL13-expression.…”

“…The mast cells recovered did not further sub-cluster in an automated fashion, and were largely marked by TPSB2 and TPSAB1 (>97%), with minimal CMA1 (<20%) expressing cells, suggesting they are largely classical MC-T cells in FGID intestine (Dwyer et al, 2021).…”